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WO2018130865A1 - Traitement des maux de tête chez les enfants et procédé - Google Patents

Traitement des maux de tête chez les enfants et procédé Download PDF

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Publication number
WO2018130865A1
WO2018130865A1 PCT/IB2017/000096 IB2017000096W WO2018130865A1 WO 2018130865 A1 WO2018130865 A1 WO 2018130865A1 IB 2017000096 W IB2017000096 W IB 2017000096W WO 2018130865 A1 WO2018130865 A1 WO 2018130865A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
coenzyme
dosage
magnesium
migraine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/000096
Other languages
English (en)
Inventor
Stephen Bradley MILNE
Samantha IRWIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hospital for Sick Children HSC
Original Assignee
Hospital for Sick Children HSC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hospital for Sick Children HSC filed Critical Hospital for Sick Children HSC
Priority to PCT/IB2017/000096 priority Critical patent/WO2018130865A1/fr
Publication of WO2018130865A1 publication Critical patent/WO2018130865A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12

Definitions

  • the present invention is directed to a composition for treating headaches and migraines, and more particularly, to a mrtraceutical preparation and methods of using same for preventative use to decrease the frequency, duration and severity of headaches and migraines in children and adults.
  • the present invention of a combination nutraceutical for children ' s headache-, bridges this gap. It allows for safe and easy use of natural, supplement with scientific and clinical, evidence for the prevention of headache in. children.
  • CAM Complementary and Alternative Medicine
  • the combination product of the present invention is a nutraeeuiieal formulated specifically for children in a day/night kit, and includes: Riboflavin lOOmg piil, Magnesium l OOrog ' pil , Coenzyme QiO SOmg piU and Melatonin 2mg pill.
  • the formulation may be a gummy, free of headache triggering aspartame and food dye.
  • melatonin may he useful tor treating headache and that it is a safe and tolerable treatment of other conditions in children 4,1 ''*' 3 ' .
  • the selected components of the present formulation ail have different mechanisms of action on the pathophysiological drivers of primary headache, outlined in detail below, supporting their use in a combination product for headache prevention. Clinical experience with these doses, and safety evidence from the literature suggest this combination will be well tolerated.
  • FAD flavin adenine dinucleotide
  • riboflavin-5'- phosphate riboflavin-5'- phosphate
  • Riboflavin is a vital in replenishing raitochondrial/ ' celiular energy production. 0" " ''
  • mitochondrial energy mechanism of action animal studies have demonstrated both analgesic and anti-inflammatory properties of riboflavin.
  • ⁇ 6 Overall, in adult studies of riboflavin, response rates are generally quoted as between 53-80%, including four small open label trials and a RCT t3 ⁇ 4 ' 6 " , ' t ''" * '_.
  • our invention contains a goal dose of 400mg of B2 divided BID for headache prophylaxis in children.
  • coenzyme q l O works to sustain mitochondrial energy stores and cellular energy metabolism through its action as an electron carrier in. the mitochondrial electron transport chain.
  • the redo activity of coenzyme Q lO allows for anii-oxidaot qualities, which may provide an inflammatory mechanism of action in migraine ' '. Recognized .-side effects of CoQ! O are accepted as rare ⁇ !%), and include anorexia, dyspepsia, nausea and diarrhea.
  • CoQlO is tolerated at .higher doses than those used in headache in mitochondrial, cardiovascular and other neurological diseases, greater than 1000mg/day.
  • Magnesium (Mg) represents a different mechanism of action in migraine pathogenesis, relating primarily to exeitotoxcity and gltaamate functioning. Magnesium, depletion leads to ' neuronal injury by causing NMDA-coupled calcium channels to open, leading to an increased, influx of calcium and release of glulamate, causing neuronal hyper-excitability and cytotoxicity via the generation nitric, oxide free radicals. A magnesium deficiency could therefore mediate migraine pathogenesis and susceptibility via excess glutamate and altered mitochondrial metabolism leading to facilitation of cortical spreading depression.
  • Melatonin is the final component in the combination product of the present invention. This supplement, produced naturally in the pineal gland, and regulated by the hypothalamus, has two important and likely mutually exclusive mechanisms of action on migraine, pathogenesis.
  • Melatonin is related to migraine via its function on sleep. Poor sleep is common among those with primary headache, comorbid in up to 80% in one study of adult nurses. " " ' In children, up to 25% of children have at least one type of sleep problem. "” Both headache and sleep share pathophysiological neuroanatomies] substrates and neurotransmitters. l u
  • sleep disruption is both a common risk and trigger for the expression of a primary headache disorder.
  • Migravent/ Dolovent is another combination product, marketed for adults.
  • Two capsules of this product consist of a proprietary blend of 876 mg (Riboflavin, Magnesium, Coenzyme Q10), and 150mg Butterbur.
  • the most recent clinical trial by the group removed the butterbur component and studied daily doses of 400mg of Riboflavin, 600mg Magnesium and 150mg Coenzyme q l O in a combination tablet. They also included multivitamin/irace elements.
  • the target group was adults with migraine aged 18-65 years old.
  • the present invention is directed to natural supplements (nutraceuSicats), formulated tor daily preventative (prophylactic ⁇ use, for reducing the severity, duration and frequency of headaches, inchtd ' ing migraine, in children and adults.
  • the invention is the first combination including melatonin, and is the first formulation with specific pediatric dosing for children aged 6 to 18 years old. Daytime and nighttime formulations are provided together in a kit.
  • the supplement of the present invention is available in ' the form of gummies, sprinkles, liquid suspensions, pills, capsules, captets or tablets or transdermal application..
  • the formulations of the present invention include daytime dosages containing Vitamin B2 (Riboilaviii), Magnesium Citrate and Coenzyme Q I O and nighttime dosages containing Vitamin B2 (Riboflavin), Magnesium Citrate, Coenzyme Q IO and melatonin.
  • Coenzyme QIO works to sustain -mitochondrial energy stores and cellular energy metabolism through its action as an electron carrier (from complexes 1 and II to complex ill) in the mitochondrial electron transport chain. Recognized side effects of CoQiO. Rare ( ⁇ I 3 ⁇ 4): Anorexia, dyspepsia, nausea and diarrhea. In one study, a rash was seen in one participant. CoQ l O is tolerated at higher doses in mitochondrial, cardiovascular and neurological diseases.
  • Magnesium is required for proper Glutamate functioning by facilitating calcium channel and N-methyl-D-aspartate f MDA) receptor blockade. Magnesium also inhibits neuroinflamtnation, nitric oxide activity, serotonin receptor affinity, and endogenous hormone regulation. Magnesium depletion leads to neuronal injury by causing NMDA-coupled calcium channels to open, leading to an. increased influx of calcium and release of glutamate, causing neuronal hyper-excttahility and cytotoxicity via the generation nitric oxide free radicals. ! Magnesium may mediate migraine pathogenesis and susceptibility via excess glutamate and altered mitochondrial metabolism leading to facilitation of cortical spreading depression.
  • Melatonin is produced in the pineal gland, and is regulated by the hypothalamus. It readily crosses all biological barriers, including the blood-brain ' barrier and the placenta. It is metabolized in the l iver to 6-hydiOxymelatooin and is excreted by the kidney forming urine metabolites called; 6- sulphatoxyraelatonin (aMT6s). " ' ! It has ami-inflammatory and antioxidant effects, inhibits Nitric oxide synthase (NOS) activity and dopamine release leading to increased membrane stability, potentiates GABA and opioid analgesia, protects against ghitamate neurotoxicity, and regulates neurovascular function by modulating 5-.HT.
  • NOS Nitric oxide synthase
  • melatonin varies with the menstrual cycle in migraine patients "" ' '168 and seasonally, in. association with migraine frequency fluctuations. ! ⁇ , '" ,! Although a recent study in pediatrics looking at urinary melatonin failed to show a. correlation with migraine, sleep disturbances (par oninias), do seem to impact the degree of migraine disability. 171 Further supporting the role of melatonin in migraine, Ramekeon, a tricyclic synthetic melatonin analog that acts specifically as an MT1 and ⁇ 2 melatonin receptor agonist, has been recently licensed in the US for insomnia. A phase il study in migraine prevention is currently under way (clinical irials.gov).
  • a method for preventing and reducing the severity, duration, and frequency of primary headaches such as migraines and tension type headaches.
  • the method includes administering to a patient 100-200 rng Vitamin B2 (Riboflavin), 100-200 mg Magnesium Citrate and 50-100 ng Coenzyme Q10, in the morning, and 100-200 mg Vitamin B2 (Riboflavin), .100-200 mg Magnesium Citrate and 50-100 mg Coenzyme Q 10 ' , and 2- 4mg of melatonin, once nightly.
  • the daily doses may be taken with or without food.
  • the nighttime doses may be taken at dinner or bedtime, with or without food.
  • kits for preventing and reducing the severity, duration and frequency of headaches the kit containing daytime and nighttime dosages.
  • Each daytime dosage may consist of two pills, each pill including .100 mg Vitamin B.2 (Riboflavin.), 100 mg Magnesium Citrate and. 50 mg Coenzyme Q10.
  • Two daytime pills may be taken with breakfast.
  • the night time dosage may consist of two pills, each pill including 100 -mg Vitamin 82 (Ribofla vin), 100 mg Magnesium Citrate, 50 mg Coenzyme Q10 and 2rng of Melatonin,
  • kits for preventing and reducing the severity, duration and frequency of headaches the kit containing daytime and nighttime dosages.
  • Each daytime dosage may consist of one pill, including 200 mg Vitamin B2 (Riboflavin), 200 mg Magnesium Citrate and iOOmg Coenzyme Q10.
  • Each night time dosage may consist of one pill, including 200 mg Vitamin B2 (Riboflavin), 200 mg Magnesium Citrate, .100 mg Coenzyme QiO and 4mg of Melatonin, This kit is may be used by teens and adults.
  • Additional vitamins that may be added to the daily formulations include up to 80 meg/day Vitamin B12 (cyanocobalamin), up to 200 mg/day Vitamin C (calcium ascorbafe), up to 2000 lU/day Vitamin D3 (eholecalcifero! and up to 4 mg/day of Folic Acid (folate). Additional vitamins that may be added to the night time formulations include 40 meg/day Vitamin B12 (cyanocobalamin), 100 mg day Vitamin C (calcium ascorbate), 1000 iU/'day Vitamin D3 (eholecalcifero! and up to 2 mg/day of Folic Acid (folate),
  • dosages listed above may be increased or decreased by up to 20% depending on the weight and age of the patient.
  • the formulations of the present invention are prepared in a pill dosage form, however it will be understood by those skilled in the art that other dosage forms may also be suitably prepared by known methods, for example, gummies, capsules, tablets, powders, pastes, liquids, transdermal patches and similar dosage forms.
  • Solid dosage forms for oral administration include gummies, caplets, capsules, tablets, pills. powders., and granules.
  • Solid dosage forms, of the present invention may be created using any pharmaceutically acceptable excipients such as fillers or extenders, binders, humectants, disrategral ing agents, wetting agents and lubricants. Suitable pharmaceutically acceptable excipients are described in "Remington: The Science and Practice of Pharmacy.” Lippincott Williams & Wilkins. Baltimore, Md. i ' 2000), incorporated herein by reference.
  • the solid dosage forms of tablets, capsules, powders and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, 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 emulsifters.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • compositions are preferably administered in spaced dosages throughout the day, for example, administered every eight to twelve hours, so as to maintain the level of active ingredients in the system of the host.
  • the dose is administered every twelve hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition permettant de traiter les maux de tête et les migraines et des procédés d'utilisation de cette composition pour une utilisation préventive en vue de diminuer la fréquence, la durée et la gravité des maux de tête et des migraines chez les enfants et les adultes.
PCT/IB2017/000096 2017-01-13 2017-01-13 Traitement des maux de tête chez les enfants et procédé Ceased WO2018130865A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2017/000096 WO2018130865A1 (fr) 2017-01-13 2017-01-13 Traitement des maux de tête chez les enfants et procédé

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2017/000096 WO2018130865A1 (fr) 2017-01-13 2017-01-13 Traitement des maux de tête chez les enfants et procédé

Publications (1)

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WO2018130865A1 true WO2018130865A1 (fr) 2018-07-19

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PCT/IB2017/000096 Ceased WO2018130865A1 (fr) 2017-01-13 2017-01-13 Traitement des maux de tête chez les enfants et procédé

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012612A1 (fr) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions a base de melatonine et d'antalgiques et utilisations
WO2011042701A1 (fr) * 2009-10-09 2011-04-14 Mathilde Valayer Compositions pour prévention ou traitement de migraines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012612A1 (fr) * 1995-10-03 1997-04-10 Interneuron Pharmaceuticals, Inc. Compositions a base de melatonine et d'antalgiques et utilisations
WO2011042701A1 (fr) * 2009-10-09 2011-04-14 Mathilde Valayer Compositions pour prévention ou traitement de migraines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GAUL C. ET AL.: "Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q10: a randomized, placebo-controlled, double-blind, multicenter trial", THE JOURNAL OF HEADACHE AND PAIN, vol. 16, no. 32, 2015, pages 1 - 8, XP055476661 *
MIANO S. ET AL.: "Melatonin to prevent migraine or tension-type headache in children", NEUROL. SCI, vol. 29, no. 4, 2008, pages 285 - 287, XP019636356 *

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