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WO2025233731A1 - Composition nutritionnelle comprenant de la vitamine b6, de la vitamine b9 et de la vitamine d pour le traitement de troubles du sommeil - Google Patents

Composition nutritionnelle comprenant de la vitamine b6, de la vitamine b9 et de la vitamine d pour le traitement de troubles du sommeil

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Publication number
WO2025233731A1
WO2025233731A1 PCT/IB2025/054246 IB2025054246W WO2025233731A1 WO 2025233731 A1 WO2025233731 A1 WO 2025233731A1 IB 2025054246 W IB2025054246 W IB 2025054246W WO 2025233731 A1 WO2025233731 A1 WO 2025233731A1
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WO
WIPO (PCT)
Prior art keywords
composition
vitamin
weight
respect
total weight
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Pending
Application number
PCT/IB2025/054246
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English (en)
Inventor
Lorenzo MELANI
Cecilia BARTOLI
Stefano GIANNELLI
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A Menarini International Licensing SA
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A Menarini International Licensing SA
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Publication of WO2025233731A1 publication Critical patent/WO2025233731A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/40—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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to a composition for oral use, in particular a nutraceutical, dietetic or nutritional composition comprising melatonin, vitamin B6, vitamin B9, vitamin D and preferably also zinc oxide or zinc salt.
  • the present invention also relates to the use of such a composition to improve sleep or to prevent or treat a sleep disorder in a subject in need thereof.
  • BACKGROUND OF THE INVENTION Sleeping is a basic human need, like eating, drinking, and breathing. Like these other needs, sleeping is vital for good health and well-being throughout an individual’s lifetime.
  • Sleep deficiency can lead to physical and mental health problems, injuries, loss of productivity, and even a greater likelihood of death.
  • sleep aids include prescription drugs, over-the-counter medications, and dietary supplements, with the first two categories often leading to multiple side-effects, becoming habit-forming or reducing their sedative effect over time, since the body can get used to them.
  • a first aspect of the present invention provides for a composition for oral use, particularly in the form of a food supplement, which comprises melatonin, vitamin B6, vitamin B9, vitamin D and preferably also zinc oxide or zinc salt.
  • composition of the invention provides for several advantages, namely: 1. reversing the concept behind “consumer” sleep products, to date mostly promoted as sleep aid for an ad hoc use, instead giving rise to the concept of sleep health to be applied on a daily basis (“daily sleep health formula”); 2. giving the customers relevant insights to apply a correct sleep hygiene, understanding which measures have to be taken to profit of the physiological sleep-wake cycle and maximize the effect of the product; 3. tackling the sleep health with a double-action approach, not only by providing exogenous melatonin in low but effective dose, but also supplementing the body with cofactors of the endogenous melatonin biosynthesis; 4.
  • the invention provides a composition according to any of the embodiments disclosed in the present specification and in the claims for use in the prevention or treatment of a sleep disorder in a subject in need thereof.
  • the invention provides the non-therapeutic use of a composition according to any of the embodiments disclosed in the present specification and in the claims to improve sleep and/or sleep quality.
  • 3 SIB – BW1350R The invention contemplates combinations of any of the foregoing aspects and embodiments of the invention.
  • DETAILED DESCRIPTION OF THE INVENTION GLOSSARY Unless otherwise defined herein, scientific, and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
  • vitamin B6 refers to a group of six chemically similar compounds, i.e., "vitamers”, that all contain a pyridine ring as their core. These are pyridoxine, pyridoxal, pyridoxamine, and their respective phosphorylated derivatives pyridoxine 5'-phosphate, pyridoxal 5'- phosphate and pyridoxamine 5'-phosphate. Pyridoxal 5'-phosphate has the highest biological activity, but the others are convertible to that form. As used herein, the term “vitamin B9” and “folate” are used as synonyms.
  • folate particularly encompasses the entire group of folate vitamin forms, comprising the naturally occurring folylpolyglutamates found in food and folic acid (pteroylglutamic acid), the synthetic form of the vitamin added as a dietary supplement to foodstuffs. “Folate” is thus the general term used for any form of the vitamin irrespective of the state of reduction, type of substitution, or degree of polyglutamylation.
  • oral thin film refers to a type of product widely understood by a person of ordinary skill in the art as having a recognised meaning in the nutraceutical or pharmaceutical fields.
  • Zinc is also intended the cationic form of Zinc: Zn 2+ .
  • the term “subject” is used to mean an animal including, but not limited to, fish, avian and mammal, preferably a human.
  • the terms "patient” and “subject” may be used interchangeably.
  • the expression "therapeutically effective amount” as used herein shall mean that dosage that provides the specific beneficial response for which the composition is administered in a subject in need of such treatment.
  • a first aspect of the present invention provides a composition for oral use comprising melatonin, vitamin B6, vitamin B9, vitamin D and preferably zinc oxide or zinc salt.
  • Example of zinc salt to use in the composition of the present invention are zinc acetate, zinc bromide, zinc carbonate, zinc chloride, zinc citrate, zinc gluconate, zinc iodide, zinc nitrate, zinc phosphate, zinc sulfate, zinc tartrate.
  • melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions.
  • the endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle.
  • Light is able to either suppress or synchronize melatonin production according to the light schedule.
  • the nychthemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite.
  • the primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures.
  • melatonin is present in a composition according to any of the embodiments disclosed herein in a concentration ranging from about 0.04% to 3.5% by weight with respect to the total weight of the composition, preferably ranging from about 0.05% to 0.8% by weight with respect to the total weight of the composition, more preferably ranging from about 0.5% to about 0.8% by weight with respect to the total weight of the composition.
  • vitamin B6 is a water-soluble vitamin that is naturally present in many foods, added to others, and available as a dietary supplement.
  • vitamin B6 represents the generic name for six compounds (vitamers) with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters.
  • Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) represent the active coenzyme forms of vitamin B6.
  • Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism. Both PLP and PMP are involved in amino acid metabolism, and PLP is also involved in the metabolism of one-carbon units, carbohydrates, and lipids. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood.
  • Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation. Among the other processes supported by Vitamin B6, it serves as a cofactor of the enzyme aromatic L-amino acid decarboxylase (AADC), 6 SIB – BW1350R responsible for the decarboxylation of levodopa (precursor of dopamine) and 5-hydroxytryptophan (precursor of serotonin and melatonin).
  • AADC aromatic L-amino acid decarboxylase
  • 6 SIB – BW1350R responsible for the decarboxylation of levodopa (precursor of dopamine) and 5-hydroxytryptophan (precursor of serotonin and melatonin).
  • vitamin B6 is present in a composition according to any of the embodiments disclosed herein in a concentration ranging from about 0.03% to 4% by weight with respect to the total weight of the composition, preferably ranging from about 0.5% to 1% by weight with respect to the total weight of the composition or ranging from about 0.03% to 0.06% by weight with respect to the total weight of the composition.
  • vitamin B9 also known as folate
  • Folate functions metabolically as an enzyme cofactor in the synthesis of nucleic acids and amino acids.
  • vitamin B9 is present in a composition according to any of the embodiments disclosed herein in a concentration ranging from about 0.004% to 0.35% by weight with respect to the total weight of the composition, preferably ranging from about 0.05% to 0.15% by weight with respect to the total weight of the composition or ranging from about 0.004% to 0.008% with respect to the total weight of the composition.
  • Vitamin D is a pro-hormone characterized by an intricate metabolism and regulation. It is well known for its role in calcium and phosphate metabolism, and in bone health. However, several studies have assessed a huge number of extra-skeletal functions, ranging from cell proliferation in some oncogenic pathways to antioxidant and immunomodulatory functions.
  • Vitamin D exerts its role by binding to VDRs (vitamin D receptors), which are located in many different tissues. Moreover, VDRs are able to bind hundreds of genomic loci, modulating the expression of various primary target genes. At brain level, Vitamin D transcriptionally activates the synthesis of Tryptophan hydroxylase 2 (TPH2).
  • vitamin D is present in a composition according to any of the embodiments disclosed herein in a concentration ranging from about 0.0002% to 0.04% by weight with respect to the total weight of the composition, preferably ranging from about 0.005% to 0.01% by weight with respect to the total weight of the composition or ranging from about 0.0002% 7 SIB – BW1350R to 0.0004% by weight with respect to the total weight of the composition.
  • vitamin D is present in the form or vitamin D2 or preferably in the form of Vitamin D3.
  • Zinc is an essential micronutrient for human metabolism that catalyzes more than 100 enzymes, facilitates protein folding, and helps regulate gene expression. Zinc is related to enzyme activity to melatonin synthesis. Melatonin has regulatory activity for zinc absorption from gastrointestinal system.
  • said zinc is zinc oxide or zinc salt present in a composition according to any of the embodiments disclosed herein in a concentration ranging from about 0.15% to 10% by weight with respect to the total weight of the composition, preferably ranging from about 2.5% to 5% by weight with respect to the total weight of the composition or ranging from about 0.15% to 0.40% by weight with respect to the total weight of the composition.
  • zinc oxide or zinc salt may be provided as at least one food-grade or pharmaceutically acceptable salt thereof.
  • the form of zinc may be selected from a group consisting of zinc acetate, zinc gluconate, zinc citrate, zinc chloride, and combinations thereof.
  • zinc oxide or zinc salt are in a sucrosomial form.
  • sucrosomial zinc oxide or zinc salt compound is a compound in which zinc oxide or zinc salt has been incorporated into a sucrosomial structure.
  • the composition of the invention may include a number of additional components.
  • the composition according to any of the embodiments disclosed herein may further include one or more additional active ingredients and/or excipients.
  • the composition comprises melatonin, vitamin B6, vitamin B9, vitamin D and zinc oxide or zinc salt as the sole active principles or ingredients.
  • composition according to the present invention can be formulated in various ways that are suitable for oral use, for example in the form of a solution, suspension, syrup, emulsion, capsules, soft capsules, tablets, pills, jellies, powders, stick, granules, or films, in particular oral thin films.
  • composition in form of a stick means a single-dose format in form of powder, granules or gel, in particular an orosoluble or orodispersible powder
  • formulations can optionally comprise any carriers, diluents and/or excipients that are known in the art to be acceptable for oral administration.
  • excipients can be selected for example from those normally known in the art and include, but are not limited to: a) carriers, such as sodium citrate and calcium phosphate; b) fillers, such as amide, lactose, microcrystalline cellulose, sucrose, glucose, mannitol and colloidal silica; c) humectants, such as glycerol; d) disintegrants, such as calcium carbonate, amides, amide derivatives, cellulose derivatives, and polyvinylpyrrolidone derivatives, sodium silicates and sodium carbonate; e) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, polymeric derivatives of cellulose, amide derivatives; f) retarders, such as paraffin, cellulose polymers, fatty acid esters; g) absorption accelerators, such as quaternary ammonium compounds; h) wetting agents and surfactants, such as cetyl alcohol and g
  • compositions of the invention such as tablets, capsules, soft capsules, gelatins, pills, and granules, can be coated by enteric, gastric or another type of coating known in the art. They can contain opacifying agents and can be of the type allowing active ingredient release only, or preferably, within a certain section of the intestine, possibly in a delayed manner. Substances that can allow such delayed use include, but are not limited to, polymers and waxes.
  • Soft capsules can accommodate the active ingredients in liquid form alone or in solutions, suspensions or emulsions of the active substances in a liquid solvent.
  • Soft capsules can be characterized by a casing that has qualities similar to those of rigid casings but is thicker and soft.
  • the composition of the invention is in a liquid form suitable for oral administration selected from emulsions, solutions or suspensions, either prepared or extemporary, syrups and elixirs.
  • Excipients suitable for the formulations according to the present 9 SIB – BW1350R invention in liquid form for oral use include, but are not limited to, diluents, such as water or other solvents, solubilizers and emulsifiers selected from ethyl alcohol, polyalcohols, propylene glycol, glycerol, polyethylene glycol and sorbitan esters. These formulations can also contain sweeteners and/or flavorings.
  • the composition of the invention is in the form of a film, such as a thin film suitable for oral administration (i.e. an oral thin film).
  • compositions particularly suitable for this type of formulation include hydroxypropyl methylcellulose (HPMC) – E464, xylitol, sucralose, aromas such as mint flavor.
  • the composition according to any of the embodiments herein disclosed is selected from a pharmaceutical composition, nutraceutical composition, dietary or nutritional foodstuff, a beverage, a food supplement, cosmetic composition, a medicament, a food or a medicated food for special medical purposes, or a medical device.
  • the invention provides for a food supplement comprising or consisting of a composition according to any of the embodiments disclosed in the present specification and in the claims.
  • the composition of the invention can be packaged in bottles, cartons and the like, or else, when the composition is in the form of powder, in vacuumized packs, cans or sachets or other suitable forms that are known to a person skilled in the art.
  • the composition or the food supplement according to the present invention are intended primarily for use by human beings but could also be used in animals. It is an object of the present invention to provide a composition according to any of the embodiments disclosed herein for use as a medicament.
  • the composition according to any of the embodiments disclosed herein can be used in the prevention and/or treatment of a sleep disorder or associated symptoms in a subject in need thereof.
  • Non limited examples of sleep disorders include insomnia, sleep apnea, or else sleep disorders associated to a medical or psychiatric condition, such as, inability to fall asleep, difficulty falling asleep, early awakening, and interrupted sleep, excessive daytime sleepiness, symptoms of 10 SIB – BW1350R shift work disorder, jet lag disorder (JLD) and symptoms thereof, dream disorders, dream disorders associated to Post-Traumatic Stress syndrome.
  • the sleep disorder is insomnia. It is also herein disclosed the use of a composition according to any of the embodiments disclosed herein for manufacturing a medicament for the prevention and/or treatment of a sleep disorder.
  • composition or food supplement described herein can also be used to restore and/or improve sleep or else to manage sleep deprivation in a subject in need, in cases where such sleep-related conditions are not classifiable as pathological.
  • the composition or food supplement of the invention may therefore be used in a non- therapeutic method for restoring or improving sleep.
  • An improvement in sleep may be characterized as an improvement in the quality of sleep (i.e., the feeling of refreshment following sleep), the duration of sleep, a decrease in the period required to attempt to induce sleep, state on waking from sleep, or a combination of the above. Therefore, in one aspect, the invention provides the non-therapeutic use of a composition or of a food supplement according to any of the embodiments disclosed herein to restore and/or to improve sleep, in particular to improve sleep quality, the duration of sleep, the period required to attempt to induce sleep, the state on waking from sleep, or a combination thereof.
  • the composition may be administered to or ingested by a subject suffering from an irregular sleep or may be administered or ingested to prevent or minimize the risk of the development of such an irregularity.
  • the compositions can also be administered to counteract sleep-wake cycle imbalances or circadian rhythm disturbances, or both, which could be associated with aging or any other cause that is non pathological.
  • the composition or food supplement according to any of the variants disclosed herein can be used to restore or improve sleep in a healthy subject.
  • a therapeutic or non-therapeutic treatment which involves the use of a composition or food supplement according to any of the embodiments disclosed herein comprises a step of administering a therapeutically effective amount of the composition or food supplement to the subject to be treated, for example once daily or two times daily or three times daily or four times daily.
  • the compositions may be orally ingested with meals; a preferred dosage is one time per day; alternatively, the composition may be administered once with each meal and once at bedtime.
  • the composition of the present invention is preferably administered shortly before the recipient wishes to induce sleep.
  • the composition is taken within one hour, 45 minutes, 30 minutes, 15 minutes or 10 minutes prior to the time the recipient wishes to induce sleep.
  • the recipient is administered the combined product immediately prior to retiring to bed. It forms part of the present invention also a kit of parts comprising melatonin, vitamin B6, vitamin B9, vitamin D and zinc oxide or zinc salt in two or more separate formulations for subsequent or simultaneous oral administration of said active ingredients.
  • the kit comprises a first composition comprising melatonin, a second composition comprising vitamin B6, vitamin B9, and vitamin D, and a third composition comprising zinc oxide or zinc salt.
  • the kit may further include additional components such as instructions for use.
  • the kit according to any of the embodiments disclosed herein can be used to restore or improve sleep or to manage sleep deprivation in a subject in need.
  • EXAMPLE COMPOSITION 1 in the form of an oral thin film Active ingredients: 12 SIB – BW1350R - from about 0.5% to about 0.8% by weight of melatonin - from about 0.5% to 1% by weight of vitamin B6 - ranging from about 0.05% to 0.15% by weight of vitamin B9 - from about 0.005% to 0.01% by weight of vitamin D - ranging from about 2.5% to 5% by weight of zinc oxide or zinc salt; Excipients comprising hydroxypropyl methylcellulose (HPMC) – E464, Xylitol, Sucralose, Mint flavor: up to 100% by weight.
  • HPMC hydroxypropyl methylcellulose
  • EXAMPLE COMPOSITION 3 in the form of thin film Active ingredients: - from about 0.6% to about 3.5% by weight of melatonin - ranging from about 0.06% to 0.35% by weight of vitamin B9 - ranging from about 2.5% to 10.5% by weight of zinc oxide or zinc salt; - from about 0.4% to 2% by weight of vitamin B6 - from about 0.002% to 0.003% % by weight of vitamin D3 Excipients up to 100% by weight.
  • EXAMPLE COMPOSITION 4 in the form of an oral thin film Active ingredients: - from about 0.5% to about 0.8% by weight of melatonin - from about 0.5% to 1% by weight of vitamin B6 13 SIB – BW1350R - ranging from about 0.05% to 0.15% by weight of vitamin B9 - from about 0.005% to 0.01% by weight of vitamin D Excipients comprising hydroxypropyl methylcellulose (HPMC) – E464, Xylitol, Sucralose, Mint flavor: up to 100% by weight.
  • HPMC hydroxypropyl methylcellulose
  • EXAMPLE COMPOSITION 6 in the form of thin film Active ingredients: - from about 0.6% to about 3.5% by weight of melatonin - ranging from about 0.06% to 0.35% by weight of vitamin B9 - from about 0.4% to 2% by weight of vitamin B6 - from about 0.002% to 0.003% % by weight of vitamin D3 Excipients up to 100% by weight. Experimental testing Introduction Melatonin is known for its effects on oxidative stress pathways. It is evident that melatonin acts as an antioxidant thanks to its free radical scavenging properties as well as by its role in activating several antioxidant enzymes.
  • Vitamin D is well known for its role in a multiplicity of physiologic processes, that earned it several authorized EFSA claims, like the one on having a role in the process of cell division or that of contributing to the normal function of immune system. Recently it’s been registered a vitamin D- SOD network that offers specific cytoprotective and antioxidative effects in MG-63 Osteosarcoma Cell, though the extent of this effect is still unclear and should be focus of future studies.
  • Zinc has, among the others, an authorized EFSA claim specifically focusing on contributing to the protection of cells from oxidative stress. In addition, it takes part in the complex of the Copper Zinc SOD (SOD1) protein.
  • Vitamin B6 has, among the others, authorized EFSA claims on contributing to normal function of the nervous system and to normal psychological function.
  • Studies in STZ-induced diabetic rats have shown the supplementation of vitamin B6 improves oxidative stress and lipid profile in diabetes.
  • vitamin B6 supplementation enhanced serum paraoxonase and arylesterase activities which might be related to a possible direct effect of this vitamin on the enzyme and/or related to its ability to reduce oxidative stress. Taking the data of this study into consideration vitamin B6 supplementation might be a promising adjunctive agent for improving oxidative stress.
  • Vitamin B9 (as folate) has, among the others, authorized EFSA claims on contributing to normal psychological function and having a role in the process of cell division.
  • the protocol can include pre-incubating the selected cellular model with the ingredients before inducing an oxidative injury by means of an oxidant agent (i.e. hydrogen peroxide, H 2 O 2 ).
  • an oxidant agent i.e. hydrogen peroxide, H 2 O 2
  • the test has been carried out evaluating at first the effect of each single ingredients, then different combinations of the five ingredients and, eventually, the effect of the mix of all the five ingredients.
  • Cell viability after the treatment has been measured, i.e. via cell viability assay like the MTT or others.
  • iPSCs Human-induced pluripotent stem cells derived from a healthy patient were differentiated into forebrain neurons and stressed with hydrogen peroxide to mimic oxidative stress conditions. In this model, we tested different compounds, alone or in combination, to investigate potential neuroprotective effects. The concentrations of the single compounds were the same in the final mix. The mix is composed of Melatonin 15.86%, Vitamin B6 (Pyridoxine) 11.10%, Vitamin B9 (Folic Acid) 1.59% ⁇ M, Vitamin D3 0.079%, and Zinc 71.37%. Percentages were assessed based on the patented final product to achieve the same mixed compound.
  • the concentrations tested were Melatonin 1 ⁇ M, Vitamin B6 (Pyridoxine) 0.7 ⁇ M, Vitamin B9 (Folic Acid) 0.1 ⁇ M, Vitamin D35 nM, and Zinc 4.5 ⁇ M.
  • the viability assay showed that the H2O2 insult led to a significant decrease in cell viability (41.8%), while the combined treatment with the tested compounds (ALL) was able to significantly counteract H2O2-induced toxicity, showing notable neuroprotective effects (ALL with Zn 216.4% and ALL without Zn 213.8%). Additionally, some of the single compounds or double combinations were able to increase neuronal viability upon stressor (Figure 1).
  • the STEMdiffTM Forebrain Neuron Differentiation Kit is used in conjunction with the STEMdiffTM Forebrain Neuron Maturation to generate a mixed population of forebrain-type (FOXG1-positive) neurons from neural progenitor cells derived from human pluripotent stem cells.
  • This kit is optimized to work with STEMdiff SMADi Neural Induction Kit, which supplies the appropriate neural progenitor cells.
  • stabilized hydrogen peroxide freshly prepared, Sigma, USA
  • Compounds preparation Melatonin (#M5250, Sigma USA) stock solution was freshly prepared at 25mg/ml in ethanol and used at 1 ⁇ M diluted in culture medium.
  • Pyridoxin/Vit B6 (#P5669, Sigma) stock solution was freshly prepared at 50 mg/ml in sterile molecular grade water and used at 0.7 ⁇ M diluted in culture medium.
  • Folic acid/ Vit B9 (#F8758, Sigma) stock solution was freshly prepared at 1 mg/ml in NaOH 1 M and used at 0.1 ⁇ M diluted in culture medium.
  • Vitamin D3 (#C9756, Sigma) stock solution was freshly prepared at 1 mg/ml in ethanol and used at 5 nM diluted in culture medium.
  • Zinc oxide (Faravelli, IT) stock solution was freshly prepared at 0.2 mg/ml in 4.7% boric acid and used at 4.5 ⁇ M diluted in culture medium.
  • Viability assay Cell viability was assessed by using Cell Titer 96 AQueous One Solution Cell Proliferation Assay (MTS, Promega). Briefly, MTS solution was added following manufacturer’s protocol and incubated until 4h at 37°C, 5% CO 2 . Then, the optical density was measured at 490 nm in a microplate reader (Spark, Tecan). 1.1. Statistical analysis Statistical analyses were performed by one-way ANOVA following Tukey’s post-hoc using PRISM software. The level of significance will be set at p ⁇ 0.05

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Abstract

La présente invention concerne une composition à usage oral, en particulier une composition nutraceutique, diététique ou nutritionnelle comprenant de la mélatonine, de la vitamine B6, de la vitamine B9, de la vitamine D et de préférence également de l'oxyde de zinc ou du sel de zinc. La présente invention concerne également l'utilisation d'une telle composition pour améliorer le sommeil ou pour prévenir ou traiter un trouble du sommeil chez un sujet en ayant besoin.
PCT/IB2025/054246 2024-05-10 2025-04-23 Composition nutritionnelle comprenant de la vitamine b6, de la vitamine b9 et de la vitamine d pour le traitement de troubles du sommeil Pending WO2025233731A1 (fr)

Applications Claiming Priority (2)

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IT202400010570 2024-05-10
IT102024000010570 2024-05-10

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WO2025233731A1 true WO2025233731A1 (fr) 2025-11-13

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PCT/IB2025/054246 Pending WO2025233731A1 (fr) 2024-05-10 2025-04-23 Composition nutritionnelle comprenant de la vitamine b6, de la vitamine b9 et de la vitamine d pour le traitement de troubles du sommeil

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080107754A1 (en) * 2006-11-08 2008-05-08 Jeff Luciano Dietary supplement and a method to enhance sleep and lucid dreaming
US20080145451A1 (en) * 1999-01-20 2008-06-19 N.V. Nutricia Composition for relieving discomfort
US20170312251A1 (en) * 2016-04-30 2017-11-02 Fairhaven Health, Llc Nutritional supplements for improving female fertility
US20190069585A1 (en) * 2017-09-01 2019-03-07 Gerald Haase Compositions of micronutrients and phytochemicals for optimal human health
CN109561727A (zh) * 2016-08-04 2019-04-02 西雅图咖米公司 健康管理组合物及其制备和使用方法
US10517322B1 (en) * 2018-03-19 2019-12-31 Life Kitchen, LLC Dietary supplement formulations for promoting sleep

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080145451A1 (en) * 1999-01-20 2008-06-19 N.V. Nutricia Composition for relieving discomfort
US20080107754A1 (en) * 2006-11-08 2008-05-08 Jeff Luciano Dietary supplement and a method to enhance sleep and lucid dreaming
US20170312251A1 (en) * 2016-04-30 2017-11-02 Fairhaven Health, Llc Nutritional supplements for improving female fertility
CN109561727A (zh) * 2016-08-04 2019-04-02 西雅图咖米公司 健康管理组合物及其制备和使用方法
US20190069585A1 (en) * 2017-09-01 2019-03-07 Gerald Haase Compositions of micronutrients and phytochemicals for optimal human health
US10517322B1 (en) * 2018-03-19 2019-12-31 Life Kitchen, LLC Dietary supplement formulations for promoting sleep

Non-Patent Citations (8)

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Title
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ARUOMA, O. I.HALLIWELL, B.: "Action of hypochlorous acid on the antioxidant protective enzymes superoxide dismutase, catalase and glutathione peroxidase", BIOCHEM. J., vol. 248, 1987, pages 973 - 976
ARUOMA, O. I.MURCIA, A.BUTLER, JHALLIWELL, B.: "Evaluation of the antioxidant and pro-oxidant actions of gallic acid and its derivatives", J. AGRIC. FOOD CHEM., vol. 41, 1993, pages 1880 - 1885
CHING, T. L.DE JONG, J.BAST, A.: "A method for screening hypochlorous acid scavengers by inhibition of the oxidation of 5- thio-2 nitrobenzoic acid: application to antiasthmatic drugs", ANAL. BIOCHEM., vol. 218, 1994, pages 377 - 381, XP024763325, DOI: 10.1006/abio.1994.1195
GUTTERIDGE, J. M. C.ROWLEY, D. A.HALLIWELL, B.: "Superoxide dependent formation of hydroxyl radicals in the presence of iron salts. Detection of ''free'' iron in biological systems using bleomycin-dependent degradation of DNA", BIOCHEM. J., vol. 199, 1981, pages 263 - 265, XP055002880, DOI: 10.1042/bj1990263
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HALLIWELL, B.GUTTERIDGE, J. M. C.ARUOMA, O. I.: "The deoxyribose method: a simple test tube assay for determination of rate constants for reaction of hydroxyl radical", ANAL. BIOCHEM., vol. 165, 1987, pages 215 - 219
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