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WO2025017570A1 - Composition bioactive synergique pour moduler l'activité de la choline déshydrogénase (chd) - Google Patents

Composition bioactive synergique pour moduler l'activité de la choline déshydrogénase (chd) Download PDF

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Publication number
WO2025017570A1
WO2025017570A1 PCT/IN2023/051064 IN2023051064W WO2025017570A1 WO 2025017570 A1 WO2025017570 A1 WO 2025017570A1 IN 2023051064 W IN2023051064 W IN 2023051064W WO 2025017570 A1 WO2025017570 A1 WO 2025017570A1
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present
composition
amino
range
salts
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Rajaram Samant
Manoj Tongra
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Celagenex Research India Pvt Ltd
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Celagenex Research India Pvt Ltd
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    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • Synergistic bioactive composition for modulating choline dehydrogenase (CHD) activity for modulating choline dehydrogenase (CHD) activity
  • the present invention relates to a novel synergistic bioactive composition for modulating choline dehydrogenase activity, useful in managing the treatment of neural tube defects (NTDs), attention and cognitive dysfunction, infant processing speed, visuospatial memory, congenital disabilities, and attention deficit hyperactivity disorder.
  • the bioactivet composition comprises exogenous blend of 2-Hydroxy-N,N,N- trimethylethanaminium or precursors thereof and Methylene tetrahydrofolate reductase (MTHFK) regulators and salts thereof in specific ratio along with pharmaceutically acceptable excipients.
  • MTHFK Methylene tetrahydrofolate reductase
  • a woman’s intake of nutrients and vitamins during pregnancy should come from a variety of foods, including Proteins, Carbohydrates, Vitamins, Minerals, Fats.
  • Prenatal vitamins are essential during pregnancy to support both women health and the health of growing baby.
  • Some of the nutrients include folic acid, iron, calcium, vitamin D, choline, omega-3 fatty acids, B vitamins, and vitamin C.
  • vitamin B9 is necessary for DNA synthesis and cell division. Maternal nutrition during pregnancy and infant nutrition in the early postnatal period (lactation) are critically involved in the development and health of the newborn infant.
  • Choline is important for regulation of gene expression, the biosynthesis of lipoproteins and membrane phospholipids and for the biosynthesis of the neurotransmitter acetylcholine; glycine betaine plays important roles as a primary intracellular osmo-protectant and as methyl donor for the biosynthesis of methionine from homocysteine, a required step for the synthesis of the ubiquitous methyl donor S-adenosyl methionine. It is observed that choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT).
  • BHMT betaine homocysteine methyltransferase
  • Choline is an essential dietary nutrient with functions like as a source of labile one carbon units (CH3, methyl); as a component of lipids including phosphatidylcholine, sphingomyelin, and lipid mediators such as platelet activating factor; and as a component of the neurotransmitter acetylcholine.
  • Human choline dehydrogenase is a nuclear encoded, mitochondrial enzyme involved in choline metabolism. From a medical point of view, human CHD is of great interest due to its association with various pathologies, including male infertility, homocystinuria (HCU) and cancer. It is observed that maternal methyl-group donor intake before and during pregnancy could possibly induce epigenetic alterations in offspring genes related to metabolism and genes important to maintain DNA methylation patterns. [Clin Epigenetics. 2017; 9: 16].
  • glycine betaine In humans and mammals, glycine betaine also plays an important role as a methyl group donor involved, for example, in the methylation of homocysteine to methionine.
  • Human CHD catalyses the oxidation of choline to betaine aldehyde, which is further oxidized to glycine betaine.
  • Human CHD is important for the catabolic utilization of choline because choline is involved in the stimulation of cholinergic neuronal activity and in restoring phosphatidylcholine levels in the neuronal membrane, thus displaying a neuroprotective action relevant for diseases such as memory and cognitive deficits.
  • maternal dietary and supplemental intake of methyl-group donors especially in early gestation, can influence infant buccal DNA methylation in genes related to metabolism, growth, appetite regulation, and DNA methylation reactions. Nutrition in the early postnatal period, lactation, can influence infant DNA methylation levels.
  • Methionine supplementation of the maternal diet improves fetal growth through enhanced protein synthesis. Therefore, need to be approached with caution because any imbalance may worsen rather than improve the supply of amino acids.
  • methionine continues to be metabolized by a series of metabolic pathways that have the nonprotein amino acid homocysteine as a central component.
  • Methionine is dependent on the availability of choline, betaine, and folic acid in the diet. Hyperhomocysteinemia during pregnancy, which is a consequence of perturbations in methionine and/or folate metabolism, has been implicated in adverse outcomes such as neural tube defects, preeclampsia, spontaneous abortion, and premature delivery.
  • choline plays a vital role in epigenetic regulation, cellular signaling, and lipid metabolism. Further research is needed to fully understand choline's role in fetal development and to establish evidence-based recommendations for optimal choline intake during pregnancy.
  • MTHFR Methylenetetrahydrofolate reductase
  • the primary object of the invention is to provide novel therapeutical approach for improving fetal development.
  • Another object of the invention is to provide effective combination of bioactive components to balance one carbon metabolism by regulating homocysteine and methionine cycle.
  • Yet another object of the invention is to provide bioavailable oral compositions for treating congenital birth defects.
  • Yet another object of the invention is to provide cost-effective, side-effect-free composition for modulating CHD activity.
  • the inventors of the instant invention carried out thorough experiments to establish significant effects of the active ingredients or vitamin or quaternary ammonium compounds or nutrients or methyl donors that ameliorate therapeutic efficacy in the treatment of congenital birth defects/ fetal development.
  • the present invention provides a bioactive composition for modulating Choline Dehydrogenase [CHD] activity comprising therapeutically active exogenous blend of 2- Hydroxy-N,N,N-trimethylethanaminium or its precursors and salts thereof and Methylenetetrahydrofolate reductase (MTHFR) regulators and salts thereof, along with pharmaceutically acceptable excipients,
  • CHD Choline Dehydrogenase
  • MTHFR Methylenetetrahydrofolate reductase
  • Figure 1 illustrates CHD protein activity in cmp (counts per minutes) for G1 to G6 test groups.
  • Figure 2 illustrates CHD protein detection by Western blot analysis for G1 to G6 test groups.
  • Figure 3 illustrates Choline plasma serum level in pg/ml for G1 to G6 test groups.
  • composition does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.
  • pharmaceutically/nutraceutically acceptable salt represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to the relatively nontoxic, inorganic, and organic acid addition salts of compounds, amino acid salt, sugar-based salt, alkali or alkaline earth metal salts, as well as hydrates, solvates, co-crystals, polymorphs and the like of the salts.
  • the salts are preferably selected from chloride, bromide, calcium, sodium, hydroxide, phosphate, acetate, fumarate, lactate, maleate, sulphate, tartrate, citrate, hydrates carbonate, gluconate, mesylate, hydrochloride, hydrobromide and glucosamine.
  • the inventors of the present invention astonishingly found that the modulation of CHD activity improves the fetal development by potentiating choline requirement and balancing the one carbon metabolism during the pregnancy.
  • the inventors developed novel composition that synergistically acts on CHD enzyme and improves the fetal development.
  • MTHFR methylenetetrahydrofolate reductase which is a key regulatory enzyme in methionine and homocysteine metabolism. It is ratelimiting folate cycle enzyme which regulates folate cycle.
  • NTD neural tube defects which are birth defects of the brain, spine or spinal cord that happen in fetuses within the first month of pregnancy.
  • the two most common NTDs are spina bifida (a spinal cord defect) and anencephaly (a brain defect).
  • the invention provides synergistic bioactive composition for modulating choline dehydrogenase activity.
  • the present invention provides composition comprising synergistic combination of biologically active compounds wherein the combination comprises exogenous blend of 2-hydroxy-N,N,N-trimethylethanaminium and/or precursors thereof and methylenetetrahydrofolate reductase MTHFR) regulators and salts thereof, present in suitable weight ratio along with pharmaceutically acceptable excipients.
  • the present invention provides a synergistic bioactive composition
  • a synergistic bioactive composition comprising combination of 2-Hydroxy-N,N,N-trimethylethanaminium and/or precursors thereof which is present in the range of 0.1-2000 mg and Methylenetetrahydrofolate reductase (MTHFR) regulators which is present in the range of 0.1-1000 mg along with pharmaceutically acceptable excipients/carriers.
  • MTHFR Methylenetetrahydrofolate reductase
  • the present invention provides composition comprising synergistic combination, wherein 2-Hydroxy-N,N,N-trimethylethanaminium or its precursors are present in the range of 1-2000 mg ; preferably 1-1000 mg; more preferably 1-500 mg by weight of total composition.
  • the 2-Hydroxy-N,N,N-trimethylethanaminium precursors are selected from the group consisting of 2-Amino-3-hydroxypropanoic acid, P-Aminoethyl alcohol, 2-Methylaminoethanol and N,N-Dimethylaminoethanol.
  • 2-Hydroxy-N,N,N-trimethylethanaminium may include phospholipid salt.
  • Phospholipid conjugated to a hydrophobic or hydrophilic molecule is safe and biocompatible.
  • the phosphate salt include calcium;2-(trimethylazaniumyl)ethyl phosphate; chloride, 2-(trimethylazaniumyl)ethyl phosphate, 2-(trimethylazaniumyl)ethyl phosphate; chloride.
  • the present invention provides composition comprising synergistic combination, wherein the methylenetetrahydrofolate reductase (MTHFR) regulators and salts thereof are present in the range of 0.1-500 mg; preferably 0.1-200 mg; more preferably 0.1-100 mg by weight of total composition.
  • MTHFR methylenetetrahydrofolate reductase
  • the methylenetetrahydrofolate reductase (MTHFR) regulators are selected from group consisting of (2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6- yl)methylamino] benzoyl]amino] pentanedioic acid; (2S)-2-[[4-[(2-Amino-4-oxo-lH-pteridin- 6-yl)methylamino]benzoyl] amino]pentanedioic acid ; (2S)-2- [ [4-[(2-Amino-5-methyl-4- oxo-l,6,7,8-tetrahydropteridin-6-yl) methylamino] benzoyl] amino] pentanedioic acid ; (2S)- 2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6
  • the present invention provides composition comprising synergistic combination of 2-Hydroxy-N,N,N-trimethylethanaminium and/or precursors thereof and Methylenetetrahydrofolate reductase (MTHFR) regulators ; wherein (MTHFR) regulators or salts thereof are optionally complexing with trimethylglycine.
  • MTHFR Methylenetetrahydrofolate reductase
  • MTHFR 2-Hydroxy-N,N,N-trimethylethanaminium and its precursors maintains the methyl group metabolism simultaneously
  • (MTHFR) regulators maintain methionine cycle and inhibits activity of CHD to meets the dietary requirements for choline and thus prevents common birth defects.
  • the composition reduces the elevated NTD risks associated with lower levels of total choline.
  • the present invention provides composition comprising synergistic combination of 2-hydroxy-N,N,N-trimethylethanaminium or precursors thereof and methylenetetrahydrofolate reductase (MTHFR) regulators; wherein 2-hydroxy-N,N,N- trimethylethanaminium or precursors thereof and (MTHFR) regulators or salts thereof are present in the weight ratio of 1 : 0.001 to 1 : 1 along with pharmaceutically acceptable excipients.
  • MTHFR methylenetetrahydrofolate reductase
  • the present invention provides composition comprising synergistic combination of 2-hydroxy-N,N,N-trimethylethanaminium or precursors thereof and methylenetetrahydrofolate reductase (MTHFR) regulators ; wherein (MTHFR) regulators or salts thereof are optionally complexing with trimethylglycine.
  • MTHFR methylenetetrahydrofolate reductase
  • the present invention provides composition comprising synergistic combination of 2-Hydroxy-N,N,N-trimethylethanaminium and precursors thereof and Methylenetetrahydrofolate reductase Q ITHFR) regulators which facilitates normal development (neurogenesis) of hippocampus of the fetus. Particularly it supports fetal brain development.
  • the present bioactive composition modifies epigenome via methylation to support integrity and stability of fetal and placental genomes.
  • the CHD enzymatic reaction achieves the dual physiological role of regulating the concentration of free choline in cells and bodily fluids and synthesizing a metabolite that is relevant to both osmo protective and methylating processes.
  • the elevated activity of choline preserves the membrane integrity through phosphatidylcholine; promotes myelin sheath formation through sphingomyelin and synaptogenesis through acetylcholine.
  • the present invention provides stable composition that provides bio active nutrients useful for fetal brain and spinal cord development, moreover the composition is useful to improve neural development of fetus by reducing incidence of birth defects.
  • the maternal intake of the present composition not only improves several pregnancy outcomes but also protects against certain neural and metabolic insults.
  • composition is useful supplement for improving cell survival, synaptic plasticity, and normal brain development of fetus. It further reduces cortisol induced stress conditions.
  • the present invention provides synergistic bioactive composition wherein two ingredients work intracellularly in synergistic way to improve one carbon metabolic cycle through modulating activity of CHD.
  • the said composition is useful in the treatment of neural tube defects (NTDs), attention and cognitive dysfunction, infant processing speed, visuospatial memory, congenital disabilities, and autism. It is also involved in the production of red blood cells and supports optimal fetal growth and development.
  • the present invention provides composition that is useful to improve cognitive function and memory in maternal and foetus.
  • terapéuticaally effective amount denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration or modulation, regulation of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or minimize at least one clinical symptom related to neural tube defects.
  • indicator/biomarker e.g., blood or serum CRP level
  • subject in need thereof pertains to a human, preferably female; more preferably female with choline and folate deficiency.
  • a human preferably female; more preferably female with choline and folate deficiency.
  • Particularly female including but not limited to adult, women planning for pregnancy, women before conception, pregnant women, conceive, lactating women, women of reproductive age.
  • treatment refers to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, downregulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, prevent, inhibit, stabilize, ameliorate, cure, heal birth defects, fetal growth.
  • the instant composition is non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects, therefore the present composition can also be used as preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.
  • Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the present invention are formulated in isomeric, geometric, enantiomeric or stereoisomeric forms.
  • the active compounds may be in the hygroscopic or non-hygroscopic form based on water affinity of the compound salts.
  • Compound or pharmaceutically acceptable salts includes, hydrates, halides like chloride, bromide, metal salts like calcium, sodium, potassium, hydroxide, phosphate; polymorphs, solvates, enantiomers or racemates. Some of the crystalline forms of the compound exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.
  • the present invention provides a synergistic bioactive composition that is present in effective amount along with pharmaceutically acceptable excipients.
  • the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethylene glycol matrix which is acceptable for use in the subject, preferably humans.
  • Excipients may also include, for example: anti adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.
  • anti adherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration
  • the present invention relates to synergistic bioactive composition, which can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • the preferable route of administration includes but not limited to sublingual, rectal, topical, parenteral, nasal, or oral.
  • the present synergistic bioactive composition can be administered to the subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, hard gel, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including
  • Synergistic bioactive composition of the present invention is suitable for oral administration and can be presented as discrete units such as capsules (e.g., soft-gel capsules), cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, syrup; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredients can also be presented in the form of a bolus, electuary or paste, bioactive bar, energy bars (candy bars), powder, energy drink, ready to drink, granule sachet.
  • the present composition can be formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films, orodispersible tablets and bioadhesive buccal tablets. It can also be prepared in the form of snack, confectionery food products, sachet, gummies.
  • the synergistic bioactive composition of the present invention is non-toxic, cost effective, enriched with bioactive ingredients, and provides safeguard against problems associated with choline deficiency without any adverse effect.
  • the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulphate, cellulose acetate, com starch, pregelatinized starch, dextrin, P-cyclodextrin, methylated-P- cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mediumchain triglycerides,
  • the diluent in the composition/formulation is present in a range of 1% to 30% by weight of the total composition/formulation.
  • the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, com starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral
  • the present invention provides synergistic bioactive composition which is useful in the treatment of neural tube defects (NTDs), attention and cognitive dysfunction, infant processing speed, visuospatial memory, congenital disabilities, and autism.
  • NTDs neural tube defects
  • attention and cognitive dysfunction attention and cognitive dysfunction
  • infant processing speed visuospatial memory
  • congenital disabilities and autism.
  • the binder in the composition/formulation is present in a range of 0.1 to 30% by weight of the composition/formulation.
  • the antioxidant is selected from tocopherol (vitamin E), sesamol, guaiac resin, methionine, beta-carotene, lycopene, lutein, zeaxanthin, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium metabisulfite (SMB), 1-camosine, propyl gallate (PG), tertiary butyl hydroquinone, cysteine (CYS), citric acid, tartaric acid, phosphoric acid and ascorbic acid.
  • vitamin E tocopherol
  • sesamol guaiac resin
  • methionine beta-carotene
  • beta-carotene beta-carotene
  • lycopene lycopene
  • lutein zeaxanthin
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxytoluene
  • SMB sodium metabisul
  • the amount of antioxidant in the composition/formulation is present in the range of 0.1 to 10% by wt. of the composition/ formulation.
  • the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.
  • the lubricant in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/formulation.
  • the solubilizing agent is selected from polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betad
  • the amount of solubilizing agent or surfactant in thecomposition/formulation ranges from 0.1% to 10% by weight of the composition/formulation.
  • the solubilizing agent or surfactant is present in a range of 0.1% to 5.0% by weight of the composition/formulation.
  • the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.
  • the glidant in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/formulation.
  • the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.
  • the stabilizer in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/ formulation.
  • the plasticizers added to coating of the formulation are selected from the group consisting of propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, acetylated monoglycerides, castor oil, mineral oil and like thereof.
  • the plasticizer in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/ formulation.
  • the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.
  • the solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/formulation 100% by weight.
  • the additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients.
  • the powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.
  • the additives are used in a range of 0.1 to 10% w/w of unit dose.
  • the present invention provides the composition/formulation comprising a therapeutic blend of 2-Hydroxy-N,N,N-trimethylethanaminium or precursors thereof and Methylene tetrahydrofolate reductase (MTHFR) regulators and salts thereof along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.
  • MTHFR Methylene tetrahydrofolate reductase
  • the present invention provides the composition/formulation wherein the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0. 1 to 25%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.
  • the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0. 1 to 25%; the lubricant is present in a range of 0.1 to
  • compositions containing compounds of the present invention can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.
  • the magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 2500 mg per day, preferably about 10 mg per day to about 1500 mg per day.
  • the present invention provides the potent composition wherein the effective unit dose for an oral administration is formulated in a range of 10 to 1500 mg.
  • the present composition can be used as infant formula as well as adult formula by varying the concentration of active ingredients. Further, it is noted that the dietician or nutritionist or certified physician, medical practitioner knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.
  • Example 1 Various compositions/formulations. i. Composition 1: Tablet / Capsule. ii. Composition 2: Tablet / Capsule. iii. Composition 3: Tablet / Capsule. iv. Composition 4: Tablet / Capsule. v. Composition 5: Tablet / Capsule. vi. Composition 6: Tablet / Capsule. vii. Composition 7: Tablet / Capsule. viii. Composition 8: Tablet / Capsule. ix. Composition 9: Tablet / Capsule. x. Composition 10: Tablet / Capsule. xi. Composition 11: Tablet/ Capsule. xii. Composition 12: Tablet / Capsule.
  • a choline dehydrogenase activity was evaluated as a function of time following the removal of female mice oocytes from antral follicles.
  • CHD was assessed by Western blotting in female mice oocytes that had been cultured for 3 hr when choline dehydrogenase activity has developed utmost. Mouse kidney lysate was run to indicate the position of the CHD band. GAPDH served as a loading control.
  • CHD protein was detected by Western blot analysis as a single band near the predicted size of 65-70 kDa, particularly 66 kDa.
  • Quantitating a western blot refers to the measurement of the signal emitted by CHD protein band(s).
  • the signal intensity of the band is directly proportional to the concentration of CHD protein.
  • Body Weight 20-30gms.
  • Lighting 12 / 12-hour light-dark cycle.
  • Feed Normal chow diet.
  • Drinking water Mice were provided with ad libitum drinking water passed through water filter system.
  • compositions G4, G5 and G6 significantly decrease the CHD enzyme activity in vitro (Fig. 3) and simultaneously enhance the choline concentration which is useful for fetal development. Moreover, this study indicates that the combination in specific ratio inhibits the degradation of choline by lowering the activity of choline dehydrogenase an important enzyme in regulation of the concentration of free choline in tissues under physiological conditions.

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Abstract

L'invention concerne une composition bioactive utile dans le traitement des défauts de tube neuronal (NTD), des troubles de l'attention et des troubles cognitifs, de la vitesse de traitement des nourrissons, de la mémoire visuospatiale, des handicaps congénitaux, du TDAH et de l'autisme. En particulier, l'invention concerne une combinaison synergique de composés biologiquement actifs, la combinaison comprenant un mélange exogène de 2-Hydroxy-N,N,N-triméthyléthanaminium ou de précurseurs et de sels de celui-ci et de régulateurs de Méthylènetétrahydrofolate réductase (MTHFR) et de sels de ceux-ci, présents dans un rapport pondéral approprié conjointement avec des excipients pharmaceutiquement acceptables.
PCT/IN2023/051064 2023-07-19 2023-11-17 Composition bioactive synergique pour moduler l'activité de la choline déshydrogénase (chd) Pending WO2025017570A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013052117A1 (fr) * 2011-10-05 2013-04-11 Golini Jeffrey M Composition à base de choline
WO2015023767A1 (fr) * 2013-08-15 2015-02-19 Board Of Regents, The University Of Texas System Formiate de calcium comme complément pour prévenir des anomalies de tube neural
US20190125828A1 (en) * 2016-03-22 2019-05-02 Balchem Corporation Compositions comprising choline
CN113230273A (zh) * 2021-05-11 2021-08-10 北京里肯营养科学研究有限公司 一种含有胆碱、b族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013052117A1 (fr) * 2011-10-05 2013-04-11 Golini Jeffrey M Composition à base de choline
WO2015023767A1 (fr) * 2013-08-15 2015-02-19 Board Of Regents, The University Of Texas System Formiate de calcium comme complément pour prévenir des anomalies de tube neural
US20190125828A1 (en) * 2016-03-22 2019-05-02 Balchem Corporation Compositions comprising choline
CN113230273A (zh) * 2021-05-11 2021-08-10 北京里肯营养科学研究有限公司 一种含有胆碱、b族维生素、叶酸、锌的防治高同型半胱氨酸血症的复方制剂

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