WO2013158837A1 - Méthodes et compositions de traitement du trouble d'hyperactivité avec déficit de l'attention - Google Patents

Méthodes et compositions de traitement du trouble d'hyperactivité avec déficit de l'attention Download PDF

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Publication number
WO2013158837A1
WO2013158837A1 PCT/US2013/037105 US2013037105W WO2013158837A1 WO 2013158837 A1 WO2013158837 A1 WO 2013158837A1 US 2013037105 W US2013037105 W US 2013037105W WO 2013158837 A1 WO2013158837 A1 WO 2013158837A1
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curcumin
lipoic acid
gallate
epigallocatechin
pharmaceutical composition
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PCT/US2013/037105
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English (en)
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David I. Scheer
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Concourse Health Sciences Llc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic 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
    • A61K31/352Heterocyclic 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 
    • A61K31/3533,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/661Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/82Theaceae (Tea family), e.g. camellia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • A61K36/906Zingiberaceae (Ginger family)
    • A61K36/9066Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4875Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder.
  • the invention provides a collection of active ingredients, such as curcumin, piperine, and epigallocatechin-3-gallate, and methods of using such active ingredients to treat attention deficit hyperactivity disorder.
  • ADHD Attention deficit hyperactivity disorder
  • Common features of patients suffering from ADHD include inattention, excessive motor activity, and impulsivity. Inattentive behavior can involve difficulty focusing on one task, failure to pay attention to details, and making careless mistakes. Excessive motor activity can include unusually frequent motion, suffering feelings of restlessness, and difficulty engaging in sedentary activities.
  • Impulsivity can involve behavior where the patient frequently interrupts conversations or others' activities, is very impatient, has difficulty waiting for things they want, blurts out inappropriate comments, shows their emotions without restraint, and acts without regard for consequences. These behavioral conditions can place the patient at risk for poor educational achievement, underemployment, and difficulty maintaining normal social relationships.
  • ADHD has been reported to be highly heritable and genetics are believed to contribute to about three-quarters of patients suffering form ADHD. Most patients suffering from ADHD had their first symptoms of the disorder during childhood. A small number of ADHD cases have been reported where the disorder was acquired after conception due to brain injury caused by toxins or physical trauma.
  • Current medical treatments for ADHD include the use of mild central nervous system stimulant drugs, such as Ritalin, Cylert, and Dexedrine. However, these medications can have multiple adverse side effects, including insomnia, loss of appetite, headaches, stomachaches, hyperactivity, drowsiness, and cardiac arrhythmia. As a result, there is a need for new therapies to treat ADHD.
  • the present invention addresses the need for new therapies to treat ADHD and provides other related advantages.
  • the invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder.
  • the methods involve administering, preferably for convenience as a mixture, a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid to a patient suffering from attention deficit hyperactivity disorder.
  • a combination of the active ingredients curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be taken together to form a pharmaceutical composition, and each of these ingredients optionally may be in the form of a pharmaceutically acceptable salt.
  • Medical kits for treating attention deficit hyperactivity disorder using a collection of the active ingredients are provided.
  • one aspect of the invention provides a method of treating attention deficit hyperactivity disorder in a patient.
  • the method comprises administering to a patent in need thereof a therapeutically effective amount of a collection of active ingredients described herein (which collectively constitute a therapeutic agent), such as two or more of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid.
  • the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.
  • the particular collection of active ingredients administered to the patient may be selected in order to achieve a desired clinical benefit.
  • the method comprises administering to a patent in need thereof a therapeutically effective amount of curcumin, piperine,
  • the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.
  • the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a collection of active ingredients described herein and optionally a pharmaceutically acceptable carrier.
  • the active ingredients may be taken together to form a therapeutic agent, such as a therapeutic agent comprising two or more of curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid.
  • the curcumin, piperine, epigallocatechin-3- gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.
  • the particular collection of active ingredients taken together to form the therapeutic agent may be selected in order to achieve a desired clinical benefit.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a therapeutic agent present in an amount for treating attention deficit hyperactivity disorder in a patient and consisting essentially of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt; and (b) optionally a pharmaceutically acceptable carrier.
  • kits for treating attention deficit hyperactivity disorder comprises a pharmaceutical composition described herein and instructions for treating attention deficit hyperactivity disorder.
  • Figure 1 shows bar graphs of baseline cognitive test scores as a function of group prior to treatment, as explained in Example 1. Bars represent group means and error bars are standard errors of the mean.
  • Figure 2 shows bar graphs of the results of the Landmark Discrimination Learning Test described in Example 1. Dogs in both groups (i.e., the control group and the group that received the cocktail) underwent a systematic training protocol of learning to select one of two identical objects on the basis of the location of a landmark. Bars indicate group means and error bars standard errors of the mean. Individual data points are also shown by circles in graphs A-E DE TAILED DESCRIPTION OF THE INVENTION
  • the invention provides methods, compositions, and medical kits for treating attention deficit hyperactivity disorder.
  • the methods involve administering a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N- acetylcysteine, benfotiamine, and lipoic acid to a patient suffering from attention deficit hyperactivity disorder.
  • the active ingredients curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be taken together to form a pharmaceutical composition, and each these active ingredients may optionally be in the form of a
  • kits for treating attention deficit hyperactivity disorder using a collection of the active ingredients described herein are also provided.
  • the term "patient” refers to organisms to be treated by the methods of the present invention.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • treating includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • the term "effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the phrase "therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metal hydroxides, alkaline earth metals hydroxides, ammonia, and compounds of formula NW , wherein W is C 1-4 alkyl, and the like.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C 1-4 alkyl group), and the like.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Cioalkyl, and Ci-C 6 alkyl, respectively.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, butyl, etc.
  • Certain compounds may exist in particular geometric or stereoisomeric forms.
  • the structure of certain compounds include asymmetric carbon atoms.
  • the isomers arising from such asymmetry e.g., all enantiomers and diastereomers
  • mixtures of such isomers e.g., a mixture of enantiomers
  • These compounds may be designated by the symbols "R” or "S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis.
  • Alkenes can include either the E- or Z-geometry, where appropriate.
  • the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • One aspect of the invention provides methods of treating attention deficit hyperactivity disorder in a patient.
  • the method comprises administering to a patent in need thereof a therapeutically effective amount a collection of active ingredients described herein, such as two or more of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid, each of which are optionally in the form of a pharmaceutically acceptable salt.
  • the method comprises administering to a patent in need thereof a therapeutically effective amount of curcumin, piperine, epigallocatechin-3-gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a
  • a therapeutically effective amount of each of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, and lipoic acid are administered to the patient.
  • a therapeutically effective amount of each of curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid are administered to the patient.
  • curcumin, piperine, epigallocatechin-3-gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.
  • the methods are contemplated to provide various benefits to patients suffering from attention deficit hyperactivity disorder.
  • exemplary benefits include improving the patient's ability to maintain mental focus on a task and reducing the frequency with which the patient becomes distracted relative to the patient's rate of distraction without therapy.
  • the patient is desirably a human, and often a male less than 19 years of age.
  • Curcumin refers to the chemical compound (lis,6is)-l,7-bis (4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione and includes (i) tautomers thereof and (ii) mixtures of (lis,6is)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione and a tautomer thereof.
  • the compound (lis,6is)-l,7-bis (4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5- dione has the chemical formula shown below.
  • Curcumin may be administered at a daily dosage of, for example, at least about 4 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or 60 mg/kg. In certain embodiments, the curcumin is administered at a daily dosage of at least 4 mg/kg.
  • the curcumin is administered at a daily dosage in the range of from about 4 mg/kg to about 60 mg/kg, from about 4 mg/kg to about 30 mg/kg, from about 4 mg/kg to about 15 mg/kg, from about 25 mg/kg to about 60 mg/kg, from about 25 mg/kg to about 40 mg/kg, from about 30 mg/kg to about 60 mg/kg, or from about 45 mg/kg to about 60 mg/kg.
  • the daily dosage of curcumin may be achieved by administering the patient a single pharmaceutical composition containing curcumin once per day. Alternatively, the daily dosage of curcumin may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing curcumin.
  • Curcumin may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.
  • Piperine is l-[(2£ ' ,4£)-5-(l,3-benzodioxol-5-yl)-l-oxo-2,4-pentadienyl]piperidine and has the chemical formula shown below.
  • Piperine may be administered at a daily dosage of, for example, at least about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg. In certain embodiments, piperine is administered at a daily dosage of at least 0.5 mg/kg. In certain other embodiments, piperine is administered at a daily dosage in the range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 3 mg/kg to about 5 mg/kg, or from about 4 mg/kg to about 5 mg/kg.
  • the daily dosage of piperine may be achieved by administering the patient a single pharmaceutical composition containing piperine once per day. Alternatively, the daily dosage of piperine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing piperine.
  • Piperine may be administered in the form of an extract of a naturally occurring composition, such as where the piperine is provided in the form of an extract of black pepper.
  • Epigallocatechin-3-gallate is [(2R,3R)-5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate and has the chemical formula shown below.
  • Epigallocatechin-3-gallate may be administered at a daily dosage of, for example, at least about 4 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or 60 mg/kg. In certain embodiments, the epigallocatechin-3-gallate is administered at a daily dosage of at least 4 mg/kg.
  • the epigallocatechin-3-gallate is administered at a daily dosage in the range of from about 4 mg/kg to about 60 mg/kg, from about 4 mg/kg to about 30 mg/kg, from about 4 mg/kg to about 15 mg/kg, from about 25 mg/kg to about 60 mg/kg, from about 25 mg kg to about 40 mg/kg, from about 30 mg/kg to about 60 mg/kg, or from about 45 mg/kg to about 60 mg/kg.
  • the daily dosage of epigallocatechin-3 -gallate may be achieved by administering the patient a single pharmaceutical composition containing epigallocatechin-3 -gallate once per day.
  • the daily dosage of epigallocatechin-3 - gallate may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing epigallocatechin-3 -gallate.
  • Epigallocatechin-3 -gallate may be administered in the form of an extract of a naturally occurring composition, such as where the epigallocatechin-3 -gallate is provided in the form of an extract of green tea.
  • N- Acetylcysteine is (R)-2-acetamido-3-sulfanylpropanoic acid, which has the structure shown below.
  • N-Acetylcysteine may be administered at a daily dosage of, for example, at least about 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, or 25 mg/kg. In certain embodiments, the N-acetylcysteine is administered at a daily dosage of at least 2 mg/kg.
  • the N-acetylcysteine is administered at a daily dosage in the range of from about 2 mg/kg to about 25 mg/kg, from about 2 mg/kg to about 15 mg/kg, from about 2 mg/kg to about 10 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 10 mg/kg to about 15 mg/kg, from about 15 mg/kg to about 25 mg/kg, or from about 20 mg/kg to about 25 mg/kg.
  • the daily dosage of N-acetylcysteine may be achieved by administering the patient a single pharmaceutical composition containing N-acetylcysteine once per day. Alternatively, the daily dosage of N-acetylcysteine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing N-acetylcysteine.
  • Benfotiamine refers to S-[(2Z)-2- ⁇ [(4-amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino ⁇ -5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate, which has the chemical structure provided below.
  • Benfotiamine may be provided in the form of a pharmaceutically acceptable salt, such as an alkali metal salt (e.g., a sodium or potassium salt), alkaline earth metal salt (e.g., a calcium salt), or ammonium salt.
  • a pharmaceutically acceptable salt such as an alkali metal salt (e.g., a sodium or potassium salt), alkaline earth metal salt (e.g., a calcium salt), or ammonium salt.
  • Benfotiamine may be administered at a daily dosage of, for example, at least about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg. In certain embodiments, the benfotiamine is administered at a daily dosage of at least 0.5 mg/kg.
  • the benfotiamine is administered at a daily dosage in the range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 3 mg/kg to about 5 mg/kg, or from about 4 mg/kg to about 5 mg/kg.
  • the daily dosage of benfotiamine may be achieved by administering the patient a single pharmaceutical composition containing benfotiamine once per day. Alternatively, the daily dosage of benfotiamine may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing benfotiamine.
  • Lipoic acid is 5-(l,2-dithiolan-3-yl)pentanoic acid and includes all stereoisomeric forms and mixtures of stereoisomeric forms. The structure of lipoic acid is shown below.
  • the lipoic acid is (R)-lipoic acid, which has the formula:
  • Lipoic acid may be administered at a daily dosage of, for example, at least about 1 mg/kg, 5 mg/kg, 10 mg/kg, or 15 mg/kg. In certain embodiments, the lipoic acid is administered at a daily dosage of at least 1 mg/kg. In certain other embodiments, the lipoic acid is administered at a daily dosage in the range of from about 1 mg/kg to about 15 mg/kg, from about 1 mg/kg to about 10 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 5 mg/kg to about 15 mg/kg, or from about 10 mg/kg to about 15 mg/kg.
  • the daily dosage of lipoic acid may be achieved by administering the patient a single pharmaceutical composition containing lipoic acid once per day. Alternatively, the daily dosage of lipoic acid may be achieved by administering to the patient multiple times per day a pharmaceutical composition containing lipoic acid.
  • the active ingredients may be administered to the patient by any medically accepted route of administration.
  • the active ingredients are administered orally.
  • the active ingredients may be administered to the patient at the same time, such as when the active ingredients are formulated into a pharmaceutical composition that is administered to the patient.
  • at least a portion of the active ingredients may be administered sequentially to the patient.
  • the amount of each active ingredient that is administered to the patient can be selected to achieve particular clinical benefits.
  • the weight percent ratio of curcumin, epigallocatechin-3-gallate, and piperine administered to a patient on a daily basis is in the range about 10-15 : 10-15 : 1.
  • the weight percent ratio of curcumin, epigallocatechin-3-gallate, and N-acetylcysteine administered to a patient on a daily basis is in the range about 2-4 : 2-4 : 1.
  • the weight percent ratio of curcumin, epigallocatechin-3-gallate, and lipoic acid administered to a patient on a daily basis is in the range about 3-6 : 3-6 : 1.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a collection of active ingredients described herein and optionally a pharmaceutically acceptable carrier.
  • the active ingredients may be taken together to form a therapeutic agent, such as a therapeutic agent comprising two or more of curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid.
  • a therapeutic agent comprising two or more of curcumin, piperine, epigallocatechin-3-gallate, N- acetylcysteine, benfotiamine, and lipoic acid.
  • the curcumin, piperine, epigallocatechin-3- gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a therapeutic agent present in an amount for treating attention deficit hyperactivity disorder in a patient and consisting essentially of curcumin, piperine, epigallocatechin-3 -gallate, and one or more of N-acetylcysteine, benfotiamine, and lipoic acid, wherein the curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, benfotiamine, and lipoic acid are each optionally in the form of a pharmaceutically acceptable salt; and (b) optionally a pharmaceutically acceptable carrier.
  • the therapeutic agent specified above is the only agent in the pharmaceutical composition that provides a therapeutic effect in treating attention deficit hyperactivity disorder.
  • the aforementioned therapeutic agent contains N-acetylcysteine.
  • the aforementioned therapeutic agent contains benfotiamine.
  • the aforementioned therapeutic agent therapeutic agent contains lipoic acid.
  • therapeutic agent consists essentially of curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, and lipoic acid, each of which are optionally in the form of a pharmaceutically acceptable salt.
  • curcumin, piperine, epigallocatechin-3 -gallate, N-acetylcysteine, benfotiamine, and lipoic acid may be administered in the form of an extract of a naturally occurring composition, such as where the curcumin is provided in the form of an extract of turmeric.
  • the pharmaceutical composition may contain an active ingredient in one of the forms (e.g., a salt form, stereoisomeric form, or extract) described in Section I above.
  • forms e.g., a salt form, stereoisomeric form, or extract
  • the curcumin is provided in the form of an extract of tumeric.
  • the epigallocatechin-3 -gallate is provided in the form of an extract of green tea.
  • the lipoic acid is (R)-lipoic acid.
  • the pharmaceutical composition may contain the active ingredients in ratios that provide particular advantages for treating attention deficit hyperactivity disorder.
  • the weight percent ratio of curcumin, epigallocatechin-3 -gallate, and piperine in the pharmaceutical composition is in the range about 10-15 : 10-15 : 1.
  • the weight percent ratio of curcumin, epigallocatechin-3-gallate, and N- acetylcysteine in the pharmaceutical composition is in the range about 2-4 : 2-4 : 1.
  • the weight percent ratio of curcumin, epigallocatechin-3-gallate, and lipoic acid in the pharmaceutical composition is in the range about 3-6 : 3-6 : 1.
  • the pharmaceutical composition may be characterized according to whether it contains an active ingredient at a concentration sufficient to provide one of the daily dosage amounts described in Section I.
  • the pharmaceutical composition contains curcumin at a concentration sufficient so that administration of a single unit dose provides the patient with at least about 4 mg/kg of curcumin.
  • Exemplary pharmaceutical compositions are provided in Tables 1 and 2 below, which list the relative amounts of the active ingredients.
  • Another aspect of the invention provides a unit dosage pharmaceutical composition, such as a tablet or capsule.
  • Tablets and capsules can be prepared based on procedures known in the art and as described below.
  • the pharmaceutical compositions desirably comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pes
  • pharmaceutically-acceptable carrier means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) algin
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin;
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the salt thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
  • the effective daily dose of the active ingredient may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. III. Medical Kits
  • kits for treating attention deficit hyperactivity disorder comprises a pharmaceutical composition described herein (such as one of pharmaceutical compositions in Section II) and instructions for treating attention deficit hyperactivity disorder.
  • the instructions may provide dosing procedures, including route of administration, dosing frequency, and other information desirable for safe and effective use of the medical kit.
  • the Curcumin Test Cocktail was formulated to include green tea extract (203 mg epigallocatechingallate or 36.3% by weight), piper nigrum extract (17 mg Bioperine, 95% piperine, 3.0% by weight), N-acetyl-Z-cysteine (85 mg, 15.3% by weight), curcumin (203 mg, 36.3% by weight) and (R)-lipoic acid (51 mg, 9.1% by weight). Control capsules were formulated without any of these active ingredients.
  • Test procedures are described below, along with a description of the apparatus used in the tests.
  • the test apparatus was a 25" x 3 ' x 4' wooden box constructed from plywood coated with melamine.
  • the box was equipped with a sliding black laminate tray containing three food wells which are covered by objects.
  • One teaspoon (approximately 4 mL) of wet dog food was formed into a ball and placed in one food well to serve as the food reward.
  • Vertical stainless steel bars (adjusted to provide openings appropriate for individual dog sizes) served as the front of the box.
  • the tester sat behind a hinged door that allowed a sliding tray to be either pushed toward the dog or obscured from the dog's view.
  • a 60W light was placed above the presentation tray to light the objects.
  • the first test session was used to establish object preferences. On each trial, the hinged door separating the tester and the dog was raised and the presentation tray was pushed forward. The left and right food wells were covered by the two objects. The food reward was placed in both the left and right food wells beneath each object. Dogs were required to displace an object to expose the food reward.
  • Ten trials were given with two objects presented simultaneously (a yellow plastic Megablock and a blue plastic ball mounted on a blue plastic coaster), and with food reward beneath both objects. The objects appeared randomly five times each on the left or right side. The preferred object was whichever object was chosen more frequently (i.e., six or more times). Subsequently, the preferred object was used as the positive stimulus.
  • each dog was given ten daily trials with the food reward beneath the designated positive object. To prevent the dogs from using olfactory cues, the food odors were smeared over both wells. Further, a piece of food was pressed inside the negative stimulus such that the dog could smell it but not see it or eat it. A correct response was recorded when dogs approached and displaced the positive stimulus. An error was committed if dogs displaced the negative object. One correction per test session was allowed, with subsequent errors resulting in immediate withdrawal of the tray and no food reward. Dogs were trained until one of two criterion levels was met: 9/10 correct on one day or 8/10 correct on two consecutive days. A maximum of 400 trials were given if a dog could not reach criterion.
  • Dogs were given 50 days of testing consisting of 12 trials/day, with the location of the reward appearing four times each in the 3 food wells. During the 50 days of testing, if an animal reached criterion at the five-second delay, the delay was increased to 10 seconds, followed by gradually increasing delay intervals. Two scores were calculated from this test - total number of errors made to reach criterion (or after 50 days of testing if criterion was not met) at the five- second delay, and maximal memory score, which represented the maximum delay interval animals could reach criterion at in the 50 days of testing. Following incremental delay interval increases over a 50 day period, dogs were given a variable delay procedure for 20 days.
  • Dogs were given either a 20, 70 or 1 10 second delay in a single day of testing, with four trials at each delay interval. Accuracy scores for each delay interval were calculated as a measure of spatial working memory. Animals were tested on the spatial non-matching to position task at both baseline and after eight months of treatment.
  • One group of dogs was given the Curcumin Test Cocktail.
  • the other group of dogs i.e., the control group
  • Two different colored pills were formulated to allow testing technicians to be blind with respect to treatment condition and yet also be able to administer the treatment. Dogs were given two capsules per day, one in the morning prior to cognitive testing and one in the afternoon, after cognitive testing was completed.
  • the landmark was moved at successively greater distances (5, 18, or 24 cm) away from the reward object, with animals required to meet criterion before progressing to testing with a longer landmark distance. Animals that could not reach criterion at any of the longer distances within 400 trials stopped testing on this stepwise protocol. Once all animals had been tested out to a 24 cm distance on the landmark

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Abstract

La présente invention concerne des méthodes, des compositions, et des kits médicaux de traitement du trouble d'hyperactivité avec déficit de l'attention. Plus particulièrement, l'invention concerne un ensemble de principes actifs, tels que la curcumine, la pipérine, l'épigallocatéchin-3-gallate, et un ou plusieurs des éléments suivants : N-acétylcysteine, benfotiamine, et acide lipoïque, ainsi que des méthodes d'utilisation de tels principes actifs dans le traitement du trouble d'hyperactivité avec déficit de l'attention. L'invention concerne également des kits médicaux de traitement du trouble d'hyperactivité avec déficit de l'attention faisant intervenir un ensemble desdits principes actifs.
PCT/US2013/037105 2012-04-18 2013-04-18 Méthodes et compositions de traitement du trouble d'hyperactivité avec déficit de l'attention WO2013158837A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2258359A2 (fr) * 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
US20110275591A1 (en) * 2004-12-01 2011-11-10 Concourse Health Sciences Llc Cocktail for modulation of alzheimer's disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110275591A1 (en) * 2004-12-01 2011-11-10 Concourse Health Sciences Llc Cocktail for modulation of alzheimer's disease
EP2258359A2 (fr) * 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline

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