WO2022214861A1 - A nutraceutical formulation - Google Patents

Abstract

The present invention discloses 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.

Description

A NUTRACEUTICAL FORMULATION

FIELD OF INVENTION

The present invention generally relates to a nutraceutical formulation. In particular, 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.

BACKGROUND ART

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. In addition, choline is needed to produce acetylcholine, an important neurotransmitter for memory, mood, muscle control and other brain and nervous systems functions.

Referring to the choline metabolism chain, choline is initially converted to phosphocholine before being converted into cytidine diphosphate-choline (CDP 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.

SUMMARY OF INVENTION

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. Preferably, the formulation further comprises alpha tocopherol.

Preferably, the phosphatidylcholine weight per intake is 100-1000mg.

Preferably, the cytidine diphosphate-choline weight per intake is 50-250mg.

Preferably, the choline alfoscerate weight per intake is 50-600mg.

Preferably, the alpha tocopherol weight per intake is 10-30mg. Another embodiment of the present invention provides use of 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.

Preferably, the formulation further comprises alpha tocopherol.

Preferably, the phosphatidylcholine weight per intake is 100-1000mg. Preferably, the cytidine diphosphate-choline weight per intake is 50-250mg.

Preferably, the choline alfoscerate weight per intake is 50-600mg. Preferably, the alpha tocopherol weight per intake is 10-30mg.

The present invention may be embodied in other specific forms without departing from its essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore indicated by the appended claims rather than by the foregoing description. All changes, which come within the meaning and range of equivalency of the claims, are to be embraced within their scope.

DETAILED DESCRIPTION OF INVENTION

The present invention generally relates to a nutraceutical formulation. In particular, 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.

Hereinafter, the nutraceutical formulation according to the present invention will be described in detail according to the preferred embodiments. It is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned without departing from the scope of the appended claims.

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. By referring to the choline metabolism chain, 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. 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. In the present invention, 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.

In the last step in the pathway, CDP choline is esterified withy diacylglycerol (DAG) by cholinephosphotransferase (CEPT) to produce phosphatidylcholine. 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.

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. In the present invention, 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.

Further, 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.

Research finding shows that supplementation of 250mg - 500mg of CDP Choline showed improved attention and psychomotor speed and reduced impulsivity compared to adolescents males who received placebo ( McGlade E, Agoston AM, DiMuzio J. et ai. The Effect of Cftieoiine Supplementation on Motor Speed and Attention in Adolescent Males Journal of Attention Disorders 2019;23{2):121~134 doi:10. 1177/1087054715593633).

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).

Double blind studies demonstrate that the supplementation of phosphatidylcholine in a normal college student lead to improvement in explicit memory due to the increase in choline supply and cholinergic functions ( Ladd SL, Sommer SA, LaBerge S, Toscano W. Effect of phosphatidylcholine on explicit memory. Clin Neuropharmacol. 1993 Dec; 16(6): 540-9. PMID: 9377589). 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. The compositions of the invention can be formulated with 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. A suitable enteric coating, which dissolves in the small intestine but not in the stomach, is cellulose acetate phthalate.

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.

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 (their esters and salts) 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. In particular, the source of the fatty acids is fish or marine oil (DHA or EPA), soybean oil or flaxseed oil. Alternatively or in combination with one of the above identified carrier, 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.

Various additives can be incorporated into the present compositions. Optional additives of the present composition include, without limitation, hyaluronic acid, starches, sugars, fats, antioxidants, amino acids, proteins, flavourings, colouring agents, hydrolysed starch(es) and derivatives thereof 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.

As used herein, the term “antioxidant” is recognized in the art and 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.

For oral administration, the 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). The tablets can be coated by methods well known in the art with, for example, sugars, films or enteric coatings.

Preparations for oral administration can be suitably formulated to give controlled release of the composition as is well known.

Unless the context requires otherwise or specifically states to the contrary, integers, steps or elements of the invention recited herein as singular integers, steps, or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or elements or integers, but not the exclusion of any other step or element or integer or group of steps, elements or integers. Thus, in the context of this specification, the term “comprising” is used in an inclusive sense and thus should be understood as meaning “including principally, but not necessarily solely”.

Claims

1. 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.

2. The nutraceutical formulation of claim 1, wherein the formulation further comprises alpha tocopherol.

3. The nutraceutical formulation of claim 1, wherein the phosphatidylcholine weight per intake is 100-1000mg.

4. The nutraceutical formulation of claim 1, wherein the cytidine diphosphate-choline weight per intake is 50-250mg.

5. The nutraceutical formulation of claim 1, wherein the choline alfoscerate weight per intake is 50-600mg.

6. The nutraceutical formulation of claim 2, wherein the alpha tocopherol weight per intake is 10-30mg.

7. Use of 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.

8. The use of nutraceutical formulation of claim 7, wherein the formulation further comprises alpha tocopherol.

9. The use of nutraceutical formulation of claim 7, wherein the phosphatidylcholine weight per intake is 100-1000mg.

10. The use of nutraceutical formulation of claim 7, wherein the cytidine diphosphate-choline weight per intake is 50-250mg.

11. The use of nutraceutical formulation of claim 7, wherein the choline alfoscerate weight per intake is 50-600mg.

12. The use of nutraceutical formulation of claim 7, wherein the alpha tocopherol weight per intake is 10-30mg.