WO2022214861A1 - A nutraceutical formulation - Google Patents

A nutraceutical formulation Download PDF

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Publication number
WO2022214861A1
WO2022214861A1 PCT/IB2021/054853 IB2021054853W WO2022214861A1 WO 2022214861 A1 WO2022214861 A1 WO 2022214861A1 IB 2021054853 W IB2021054853 W IB 2021054853W WO 2022214861 A1 WO2022214861 A1 WO 2022214861A1
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WO
WIPO (PCT)
Prior art keywords
choline
nutraceutical formulation
formulation
weight per
phosphatidylcholine
Prior art date
Application number
PCT/IB2021/054853
Other languages
English (en)
French (fr)
Inventor
Kor Seng @ Chan Kok Seng TAN
Bi Fah WONG
Original Assignee
Stellar Biomolecular Research Gmbh
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 Stellar Biomolecular Research Gmbh filed Critical Stellar Biomolecular Research Gmbh
Priority to CN202180001580.4A priority Critical patent/CN115443074A/zh
Priority to EP21730452.6A priority patent/EP4090174A1/en
Publication of WO2022214861A1 publication Critical patent/WO2022214861A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention generally relates to a nutraceutical formulation.
  • the present invention describes a nutraceutical formulation comprising three types of choline containing molecules for supporting healthy cell membrane, cognitive functions, lipid transport and reduction of plasmatic homocysteine.
  • Choline is a nutrient obtained through both dietary intake and endogenous synthesis. Our body needs choline to synthesize phosphatidylcholine and sphingomyelin, two major phospholipids vital for cell membranes.
  • Phosphatidylcholine (PC) is a molecule that contains two fatty acids attached to a glycerol backbone with a phosphate group and choline. All plant and animal cells need choline to preserve their structural integrity.
  • choline is needed to produce acetylcholine, an important neurotransmitter for memory, mood, muscle control and other brain and nervous systems functions.
  • choline is initially converted to phosphocholine before being converted into cytidine diphosphate-choline (CDP choline).
  • CDP choline cytidine diphosphate-choline
  • the conversion of phosphocholine to CDP choline is the slowest step in the choline metabolism chain.
  • CDP choline is the choline form produced after the rate-limiting step and has the ability to cross blood-brain barrier and reach the central nervous system.
  • Choline alfoscerate (Alpha GPC) are obtained in the body by the decomposition of phosphatidylcholine. Enzyme reactions in choline pathways are bidirectional, hence fortification of Alpha GPC allows phosphatidylcholine to be used for other purpose instead of broken down into choline. Alpha GPC enters choline pool at different point in choline pathways and also have the ability to cross blood-brain barrier and reach central nervous system.
  • the present invention suggests a nutraceutical formulation which acts as a dietary supplement to increase bioavailability of free choline that is essential for the synthesis of neurotransmitter acethylcholine and supports healthy cell membrane, cognitive functions, lipid transport and reduction of plasmatic homocysteine.
  • An embodiment of the present invention provides a nutraceutical formulation, comprising phosphatidylcholine, cytidine diphosphate-choline, and choline alfoscerate, characterized in that, combination of the phosphatidycholine with cytidine diphosphate-choline and choline alfoscerate having synergistic effect in increasing choline bioavailability for supporting cognitive functions and cellular health.
  • the formulation further comprises alpha tocopherol.
  • the phosphatidylcholine weight per intake is 100-1000mg.
  • the cytidine diphosphate-choline weight per intake is 50-250mg.
  • the choline alfoscerate weight per intake is 50-600mg.
  • the alpha tocopherol weight per intake is 10-30mg.
  • a nutraceutical formulation comprising phosphatidylcholine, cytidine diphosphate-choline and choline alfoscerate, for the treatment of disease or condition related to the aggregation of b-amyloid, Alzheimer’s disease, stroke, to improve blood-brain barrier function, to improve blood-brain barrier transport of an active agent across the blood-brain barrier, to improve or maintain cognitive health, to provide neuro protection, to facilitate neural development or to facilitate cerebral metabolism, such that one or more of the conditions are treated, improved or facilitated.
  • the formulation further comprises alpha tocopherol.
  • the phosphatidylcholine weight per intake is 100-1000mg.
  • the cytidine diphosphate-choline weight per intake is 50-250mg.
  • the choline alfoscerate weight per intake is 50-600mg.
  • the alpha tocopherol weight per intake is 10-30mg.
  • the present invention generally relates to a nutraceutical formulation.
  • the present invention describes a nutraceutical formulation which consists of three types of choline containing molecules for supporting healthy cell membrane, cognitive functions, lipid transport and reduction of plasmatic homocysteine.
  • the present invention discloses nutraceutical formulation which comprises a combination of three main active ingredients which are three types of choline- containing molecules such as choline alfoscerate (Alpha GPC), cytidine diphosphate-choline (CDP Choline), and phosphatidylcholine along with alpha tocopherol.
  • Choline is a nutrient obtained through both dietary intake and endogenous synthesis, and it is used for the synthesis of the neurotransmitter acethycholine and also involved in methyl-group metabolism, particularly in the liver, because it is a major dietary source of methyl groups via its irreversible oxidation to betaine and the subsequent synthesis of S-adenosylmethionine.
  • Liver is the major site of choline metabolism, where it is found primarily as phosphatidylcholine, it is important for the maintenance of phosphatidylcholine supply within the liver.
  • choline is initially converted to phosphocholine by choline kinase (CK), using ATP as a phosphate donor.
  • An enzyme called phosphocholine cytidylyltransferase (CCT) uses cytidine triphosphate (CTP) to convert phosphocholine into CDP choline.
  • CTP cytidine triphosphate
  • the conversion of phosphocholine to CDP choline is the slowest step in the choline metabolism chain.
  • CDP choline is included in the formulation of the present invention because it is the choline form produced after the rate-limiting step and has the ability to cross the blood-brain barrier and reach the central nervous system.
  • CDP choline is more than a choline source; it contains equimolar amounts of choline and cytidine which will help to increase the plasma uridine nucleotides and choline in the body.
  • Nucleotide uridine is a key factor in synaptic strength and neural connectivity.
  • CDP choline serves as a precursor to nucleotide uridine and nootropic ingredients. Uridine, along with CDP choline, promotes the growth of new dopamine receptors in the brain by activating D1 and D2 receptor signaling.
  • CDP choline is esterified withy diacylglycerol (DAG) by cholinephosphotransferase (CEPT) to produce phosphatidylcholine.
  • DAG diacylglycerol
  • CEPT cholinephosphotransferase
  • Essential fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are involved in the creation of DAG.
  • Phosphatidylcholine is the end product of the CDP choline pathway, most choline in the body and brain are in the form of phosphatidylcholine, it serves as a reservoir for choline.
  • Phosphatidylcholine involves in the hepatic transport of VLDL (very low density lipoproteins) and maintenance of the cell membrane integrity that is vital to all the basic biological processes. Phosphatidylcholine also serve as an excellent emulsifier that help to enhance the bioavailability of nutrients (in this case alpha GPC, CDP choline and alpha tocopherol) with which it is co-administered.
  • VLDL very low density lipoproteins
  • Alpha GPC are obtained in the body by the decomposition of phosphatidylcholine. Enzyme reactions in choline pathways is bidirectional, fortification of Alpha GPC in the formulation allow phosphatidylcholine to be used for other purpose instead of broken down into choline.
  • Alpha GPC enter choline pool at different point in choline pathways and also have the ability to cross the blood-brain barrier and reach central nervous system.
  • Alpha GPC serves as a potent nootropic ingredient and for sustenance of choline uptake by an aging brain.
  • Alpha GPC has distinct roles besides the ability to cross blood-brain barrier to directly increase the acetylcholine level within the central nervous system.
  • Alpha GPC also serves as a precursor for biosynthesis of neuronal cell phospholipids, and further augments choline pool to produce betaine which function is to reduce homocysteine level in the blood.
  • the different kinetics and interaction with choline pathways, the fortification of Alpha GPC and CDP Choline in the formulation will allow the upregulation of the CDP Choline pathways and turnover of the phosphatidylcholine cycle; which then allow phosphatidylcholine to be utilised lipid transport, formation of phosphatidylserine, sphingomyelin, and support cellular membrane structure and functions rather than breakdown to augment the choline pool, and also offer higher availability of choline for acetylcholine synthesis and other metabolic functions.
  • the formulation also comprises an active form of fat-soluble antioxidants such as alpha tocopherol.
  • Alpha tocopherol major biological role is protecting polyunsaturated fats and other components of the cell membrane from reactive oxygen species and free radicals.
  • Alpha tocopherol plays various role in supporting neurologic functions, cardiovascular health, and liver, primarily by protecting the cells from damage associated with oxidative stress. It has been found that alpha tocopherol promote healthy brain ageing, delay Alzheimer’s disease related functional decline, increase the oxidative resistance in vitro, prevent atherosclerotic plaque formation and prevent liver fibrosis driven by oxidative damage.
  • Alpha tocopherol serves as antioxidant that protects cell membranes, proteins, and DNA from oxidation and thereby contributes to cellular health.
  • Alpha tocopherol provides stability to the composition against lipid oxidation and limit the conversion of choline to trimethylamine (TMA) and trimethylamine n-oxide (TMAO) and this will prolong the product quality and reduce the risk of adverse effect caused by high concentration of choline. Bioavailability of alpha tocopherol also increases with the presence of phospholipid.
  • Each ingredient has synergistic actions and standalone actions to support the structural integrity of cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signalling, and lipid and cholesterol transport and metabolism.
  • the general adequate intake of choline for adults is 530mg per day for males, 425mg per day for females, and the daily upper limit is 3500mg per day.
  • a nutraceutical formulation of the present invention contains the following: a. Phosphatidylcholine providing 13.7% choline by weight. b. CDP Choline providing 21.4% choline by weight. c. Alpha GPC providing 40.3% choline by weight.
  • a randomized controlled trial with supplementation of Alpha GPC at 400mg, three times daily, divided dosage for three months shows cognitive and functional improvement in the treated group versus placebo (De Jesus Moreno Moreno M. Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clin Ther. 2003 Jan;25(1):178-93. doi: 10.1016/s0149-2918(03)90023-3. PMID: 12637119).
  • the choline containing composition is also specifically formulated for lipid metabolism, reduction of free fatty acid build-up at site of stroke induced nerve damage, to dissolve blood clots, conditions related to aggregation of b-amyloid, and Alzheimer’s disease.
  • the preferred method of administration is oral to allow the formulation to be consumed in divided dosages with dosing interval.
  • compositions of the invention can be formulated with suitable carriers such as starch, sucrose, or lactose in tablets, capsules, solutions, syrups and emulsions.
  • suitable carriers such as starch, sucrose, or lactose in tablets, capsules, solutions, syrups and emulsions.
  • the tablet or capsule of the present invention can be coated with an enteric coating that dissolves at a pH of about 6.0 - 7.0.
  • Formulation of the compositions of the invention into a soft gel capsule can be accomplished by many methods known in the art. Often the formulation will include an acceptable carrier, such as an oil, or other suspending or emulsifying agent.
  • an acceptable carrier such as an oil, or other suspending or emulsifying agent.
  • Suitable optional carriers include but are not limited to, for example, fatty acids, esters and salts thereof, that can be derived from any source, including, without limitation, natural or synthetic oils, fats, waxes or combinations thereof. Moreover, the fatty acids can be derived, without limitation, from non-hydrogenated oils, partially hydrogenated oils, fully hydrogenated oils or combinations thereof.
  • Non limiting exemplary sources of fatty acids include seed oil, fish or marine oil, canola oil, vegetable oil, safflower oil, sunflower oil, nasturtium seed oil, mustard seed oil, olive oil, sesame oil, soybean oil, corn oil, peanut oil, cottonseed oil, rice bran oil, babassu nut oil, palm oil, low erucic rapeseed oil, palm kernel oil, lupin oil, coconut oil, flaxseed oil, evening primrose oil, jojoba, wheat germ oil, tallow, beef tallow, butter, chicken fat, lard, dairy butterfat, shea butter or combinations thereof.
  • Specific non-limiting exemplary fish or marine oil sources include shellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy, herring, trout, sardines or combinations thereof.
  • the source of the fatty acids is fish or marine oil (DHA or EPA), soybean oil or flaxseed oil.
  • beeswax can be used as a suitable carrier, as well as suspending agents such as silica (silicon dioxide).
  • the compositions of the invention can further include various ingredients to help stabilize, or help promote the bioavailability of the components of the beneficial compositions of the invention or serve as additional nutrients to an individual's diet. Suitable additives can include vitamins and biologically-acceptable minerals.
  • Non-limiting examples of vitamins include vitamin A, B vitamins, vitamin C, vitamin D, vitamin K and folic acid.
  • Non-limiting examples of minerals include iron, calcium, magnesium, potassium, copper, chromium, zinc, molybdenum, iodine, boron, selenium, manganese, derivatives thereof or combinations thereof. These vitamins and minerals can be from any source or combination of sources, without limitation.
  • Non-limiting exemplary B vitamins include, without limitation, thiamine, niacinamide, pyridoxine, riboflavin, cyanocobalamin, biotin, pantothenic acid or combinations thereof.
  • compositions comprising the compositions of the invention can be manufactured by methods of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes.
  • the compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries that facilitate processing of the compositions into preparations that can be used.
  • antioxidant refers to synthetic or natural substances that prevent or delay the oxidative deterioration of a compound.
  • exemplary antioxidants include tocopherols, flavonoids, catechins, superoxide dismutase, lecithin, gamma oryzanol; vitamins, such as vitamins A, C (ascorbic acid) and beta-carotene; natural components such as camosol, camosic acid and rosmanol found in rosemary and hawthorn extract, proanthocyanidins such as those found in grapeseed or pine bark extract, and green tea extract.
  • compositions of the invention can take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.
  • Preparations for oral administration can be suitably formulated to give controlled release of the composition as is well known.

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Mycology (AREA)
  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Botany (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IB2021/054853 2021-04-06 2021-06-03 A nutraceutical formulation WO2022214861A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202180001580.4A CN115443074A (zh) 2021-04-06 2021-06-03 营养配制品
EP21730452.6A EP4090174A1 (en) 2021-04-06 2021-06-03 A nutraceutical formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2021001876 2021-04-06
MYPI2021001876 2021-04-06

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WO2022214861A1 true WO2022214861A1 (en) 2022-10-13

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PCT/IB2021/054853 WO2022214861A1 (en) 2021-04-06 2021-06-03 A nutraceutical formulation

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EP (1) EP4090174A1 (zh)
CN (1) CN115443074A (zh)
WO (1) WO2022214861A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114415A1 (en) * 2001-12-14 2003-06-19 Wurtman Richard J. Compositions and methods for treating and preventing memory impairment using citicoline
US20110008495A1 (en) * 2009-07-09 2011-01-13 Nawgan Products, Llc Liquid dietary supplement composition
US8486889B1 (en) * 2001-09-07 2013-07-16 Advanced Medical Instruments Composition and method for the treatment and prevention of endothelial dysfunction
US20200046660A1 (en) * 2016-09-29 2020-02-13 Nestec S.A. Omega 3 fatty acids and choline as neuroprotectant in patients with no dementia

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070004670A1 (en) * 1998-07-31 2007-01-04 Richard Wurtman Compositions containing citicoline, and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8486889B1 (en) * 2001-09-07 2013-07-16 Advanced Medical Instruments Composition and method for the treatment and prevention of endothelial dysfunction
US20030114415A1 (en) * 2001-12-14 2003-06-19 Wurtman Richard J. Compositions and methods for treating and preventing memory impairment using citicoline
US20110008495A1 (en) * 2009-07-09 2011-01-13 Nawgan Products, Llc Liquid dietary supplement composition
US20200046660A1 (en) * 2016-09-29 2020-02-13 Nestec S.A. Omega 3 fatty acids and choline as neuroprotectant in patients with no dementia

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DE JESUS MORENOMORENO M.: "Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial", CLIN THER., vol. 25, no. 1, January 2003 (2003-01-01), pages 178 - 93, XP055635748, DOI: 10.1016/S0149-2918(03)90023-3
LADD SLSOMMER SALABERGE STOSCANO W: "Effect of phosphatidylcholine on explicit memory", CLIN NEUROPHARMACOL, vol. 16, no. 6, December 1993 (1993-12-01), pages 540 - 9, XP055568419, DOI: 10.1097/00002826-199312000-00007
MARIA DE JESUS MORENO MORENO ET AL: "Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: A multicenter, double-blind, randomized, placebo-controlled trial", CLINICAL THERAPEUTICS, vol. 25, no. 1, 1 January 2003 (2003-01-01), AMSTERDAM, NL, pages 178 - 193, XP055635748, ISSN: 0149-2918, DOI: 10.1016/S0149-2918(03)90023-3 *
MCGLADE EAGOSTON AMDÍMUZIO J: "The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males", JOURNAL OF ATTENTION DISORDERS, vol. 23, no. 2, 2019, pages 121 - 134
MCGLADE ERIN ET AL: "The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males", JOURNAL OF ATTENTION DISORDERS, vol. 23, no. 2, 1 January 2019 (2019-01-01), US, pages 121 - 134, XP055865566, ISSN: 1087-0547, Retrieved from the Internet <URL:https://journals.sagepub.com/doi/pdf/10.1177/1087054715593633> DOI: 10.1177/1087054715593633 *
S L LADD ET AL: "Effect of phosphatidylcholine on explicit memory", CLINICAL NEUROPHARMACOLOGY., vol. 16, no. 6, 1 December 1993 (1993-12-01), US, pages 540 - 549, XP055568419, ISSN: 0362-5664, DOI: 10.1097/00002826-199312000-00007 *

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EP4090174A1 (en) 2022-11-23
CN115443074A (zh) 2022-12-06

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