Oral Formulations Containing Enriched Polyphenolic Compounds together with a Form of Creatine, a Source of Choline and Trisodium Citrate

Abstract

The oral supplements of the present invention utilize phenolic compounds in combination with creatine, choline, and trisodium citrate, wherein when taken together result in enhanced cellular permeation in comparison to cellular permeation in the absence of the other compounds of the combination leading to improved brain and/or physical functioning.

Claims

1. An oral dietary supplement comprising: a plant extract enriched in polyphenols wherein the plant extract enriched in polyphenols is extracted and selected from the group consisting of polyphenol-containing fruits, fibrous edibles, beans, nuts, spices, teas, vegetables, flowers and grasses and wherein the polyphenols are selected from the group consisting of monomers, dimers, trimers, oligomers and polymers; a creatine derivative; a choline; and trisodium citrate.

2. The oral dietary supplement of claim 1 wherein the polyphenols are selected from the group consisting of anthocyanins, phenolic acids, lignans, flavonoids and proanthocyanins, the creatine derivative is selected from the group of creatine itself, creatine monohydrate, creatine salts, creatine esters, creatine phosphoryl esters and their salts, and creatine chelates, and the choline is a choline derivative selected from the group consisting of choline itself, choline salts, choline esters and choline phosphoryl esters.

3. The oral dietary supplement of claim 1 or 2 wherein the plant extract enriched in polyphenols is extracted and selected from the group consisting of acai, aronia, bilberries, blueberries, cranberries, chokeberries, coffee berries, currants, red currents, black currents, black raspberries, elderberries, grapes, mangos, marionberries, peaches, pomegranate, plums, prunes, raspberries and strawberries, the fibrous edibles are selected from the group consisting of sorghum, radish, potato, rutabaga and turnip, the beans are selected from the group consisting of pinto beans, red beans and kidney beans, the nuts are selected from the group consisting of hazelnuts, pecans, pistachios, and walnuts, the spices are selected from the group consisting of cinnamon, curcumin, turmeric and pepper seeds, and the vegetables are selected from the group consisting of artichokes, asparagus, carrots, endives, olives, onions, spinach, shallots, red lettuce, and pepper.

4. The oral dietary supplement of claim 1 or 2, wherein the plant extract enriched in polyphenols is extracted and selected from the group consisting of acai, aronia, bilberries, blueberries, cranberries, chokeberries, coffee berries, black currants, black raspberries, elderberries, grapes, peaches, mangosteen, pomegranate, plums, prunes, raspberries and strawberries.

5. The oral dietary supplement of claim 1, wherein the creatine derivative is selected from the group consisting of creatine itself and salts thereof.

6. The oral dietary supplement of claim 1 or 2, wherein the choline comprises α-GPC.

7. The oral dietary supplement of claim 1, 2 or 5 further comprising polyethylene glycol.

8. The oral dietary supplement of claim 7, wherein the creatine derivative comprises creatine hydrochloride.

9. The oral dietary supplement of claim 1, 2 or 5 wherein the plant extract enriched in polyphenols contains at least 25 mg of polyphenols.

10. The oral dietary supplement of claim 1 or 2, wherein the creatine derivative comprises disodium phosphocreatine, the plant extract comprises a blueberry extract containing at least 30% total phenols, and a daily dosage of the supplement comprises from 100-350 mg of the α-GPC, 300-750 mg of the disodium phosphocreatine, 100-250 mg of blueberry extract and 10-300 mg trisodium citrate.

11. The oral dietary supplement according to claim 10, wherein the supplement is in a form selected from the group consisting of encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules and beverages.

12. The oral dietary supplement of claim 1 or 2, wherein the creatine derivative comprises disodium phosphocreatine, the plant extract comprises a blueberry extract containing at least 30% total phenols, and a daily dosage of the supplement comprises 250 mg of the α-GPC, 500 mg of the disodium phosphocreatine, 100 mg of the blueberry extract and 125 mg of the trisodium citrate.

13. The oral dietary supplement according to claim 12 wherein the supplement is in a form selected from the group consisting of encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules and beverages.

14. The oral dietary supplement of claim 1 or 2, wherein the creatine derivative comprises disodium phosphocreatine, the plant extract comprises a blueberry extract containing at least 30% total phenols, and a daily dosage of the supplement comprises from 25-350 mg of the α-GPC, 100-750 mg of the disodium phosphocreatine, 25-250 mg of blueberry extract and 10-300 mg trisodium citrate.

15. The oral dietary supplement according to claim 14, wherein the supplement is in a form selected from the group consisting of encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules and beverages.

16. The preferred oral dietary supplement of claim 1 or 2, wherein the creatine derivative comprises disodium phosphocreatine, the plant extract comprises a blueberry extract containing at least 30% total phenols, and a daily dosage of the supplement comprises 63 mg of the α-GPC, 250 mg of the disodium phosphocreatine, 50 mg of the blueberry extract and 30 mg of the trisodium citrate.

17. The oral dietary supplement of any of claim 1 or 2, wherein the plant extract enriched in polyphenols comprises a blueberry extract whose bioavailability is enhanced by the presence trisodium citrate.

18. The oral dietary supplement of any of claim 1 or 2, wherein the choline comprises α-GPC whose bioavailability is enhanced by the presence of the trisodium citrate.

19. The oral dietary supplement of any of claim 1 or 2, wherein the plant extract enriched in polyphenols comprises a blueberry extract, the choline comprises α-GPC, and the creatine derivative comprises disodium phosphocreatine whose bioavailability is enhanced by the presence of the α-GPO, the blueberry extract and the trisodium citrate due to their respective and combined enhanced bioavailability effects.

20. A method of promoting health of an individual person comprising providing the oral supplement of any of claim 1, 5, 6, 7, 8 or 13 to the person and administering the oral supplement.

21. The use of the oral supplement of claim 20 resulting in improved mental and physical functions for the individual consuming the oral supplement.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 illustrates the permeability of α-GPC through a Caco2 monolayer in the presence and absence of trisodium citrate incorporating study data summarized in Table 1.

[0034] FIG. 2 illustrates the permeability of α-GPC through a Caco2 monolayer in the presence and absence of blueberry extract incorporating study data summarized in Table 2.

[0035] FIG. 3 illustrates the permeability of α-GPC through a Caco2 monolayer in the presence and absence of blueberry extract incorporating study data summarized in Table 3.

[0036] FIG. 4 illustrates cumulative polyphenol permeation through a Caco2 membrane based on study data summarized in Table 4.

SUMMARY OF THE INVENTION

[0037] The compositions and methods of the present invention utilize phenolic compounds in combination with creatine (most preferably creatine phosphate and/or creatine hydrochloride), together with choline (most preferably in the form of α-glycerolphosphorylcholine (“α-GPC”) or phosphatidylcholine (“PC”)), and trisodium citrate, wherein taken together in an oral supplement, the phenolic, creatine, choline and trisodium citrate components result in improved mental acuity, and/or physical cellular permeation in comparison to cellular permeation in the absence of the other compounds of the combination.

[0038] The most preferred form of choline is α-GPC whose functionality is particularly enhanced by presence of trisodium citrate. The most preferred form of creatine is disodium phosphocreatine which provides cellular phosphocreatine, the main form of creatine in the mammalian body. The most preferred phenolic compound combination is a highly purified and standardized blueberry extract whose bioavailability and functionality are also enhanced by the addition of trisodium citrate. Taken together the unique combination provides a potent and efficient formulation for use in enhancing both physical and mental functions and activities, such that unexpectedly decreased daily dosage amounts of the constituents are required as compared to prior state of the art dosages.

DETAILED DESCRIPTION OF THE INVENTION

[0039] The compositions and methods of the present invention utilize phenolic compounds in combination with creatine (most preferably creatine phosphate and/or creatine hydrochloride), together with choline (most preferably in the form of α-glycerolphosphorylcholine (“α-GPC”) or phosphatidylcholine (“PC”)), and trisodium citrate, wherein taken together in an oral supplement, the phenolic, creatine, choline and trisodium citrate components result in improved mental acuity, and/or physical cellular permeation in comparison to cellular permeation in the absence of the other compounds of the combination.

[0040] The most preferred form of choline is α-GPC whose functionality is particularly enhanced by presence of trisodium citrate. The most preferred form of creatine is disodium phosphocreatine which provides cellular phosphocreatine, the main form of creatine in the mammalian body. The most preferred phenolic compound combination is a highly purified and standardized blueberry extract whose bioavailability and functionality are also enhanced by the addition of trisodium citrate. Taken together the unique combination provides a potent and efficient formulation for use in enhancing both physical and mental functions and activities, such that unexpectedly decreased daily dosage amounts of the constituents are required as compared to prior state of the art dosages.

[0041] The phenolic component(s) are preferably obtained from purified plant extracts together with and compositions enriched in anthocyanins from plant materials that naturally contain anthocyanins, although synthetically derived sources are contemplated for the phenolic compounds of the present invention. When using plant extracts, the compositions of the present invention is not limited to the particular part of the plant used to prepare the phenolic component. Examples of plants and fruits that may be used in the preparation of the purified extracts of the present invention include any plant, including fruits and vegetables, that contains anthocyanins, including blueberries, bilberries, blackberries, strawberries, red currants, black currants, cranberries, cherries, raspberries, grapes, currants, elderberries, hibiscus flowers, bell peppers, red cabbage, purple corn, and violet sweet potatoes. Most colored fruits and vegetables are known to contain anthocyanins and proanthocyanidins.

[0042] The most preferred form of the creatine utilized in the compositions of the present invention is a phosphocreatine disodium salt. In these salts, the creatine is by weight approximately half of the phosphocreatine salt utilized in the present invention. Another preferred form of creatine is a dry creatine hydrochloride such as the Creatine HCl product available from BulkSupplements.com whose address is 7511 Eastgate Road, Henderson, Nev. 89011, which 500 g labeled product teaches a single serving size as 750 mg. Creatine monohydrate is also available from BulkSupplements.com, with product labels teaching a single serving as 2,500 mg.

[0043] However, as used herein, the term “creatine derivative” is intended to broadly encompass food grade, ingestible creatine or a creatine-based compound. In preferred embodiments of the preparations of the present invention, the creatine derivative is selected from the group consisting of creatine monohydrate, creatine hydrochloride, creatine phosphate, mixtures thereof and salts thereof. The selected compound(s) is advantageously administered orally in an amount from about 0.25 grams/day to less than 1.0 grams/day of the creatine moiety(ies)/creatine active ingredient(s) of the selected creatine derivative(s).

[0044] The compositions of the present invention are preferably made available as an encapsulated power, but may also be manufactured in any of a number of ingestible forms such as tablets, pills, powders, lozenges, elixirs, gummies, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules. It may be possible that to also supplement a diet by utilizing the compositions of the present invention in the form of suppositories, sterile injectable solutions and sterile packaged powders.

Example 1

[0045] A most preferred embodiment of a supplement of the present invention, the following powder ingredients are blended in the following w/w percentages:

TABLE-US-00001 Creatine Di-Sodium phosphate 54.68% Alpha GPC 27.05% Blueberry powder extract 10.82% Trisodium citrate 6.45% Magnesium stearate 1.00% Total 100.00%

[0046] A single dose capsule of this formulation containing about 930 mg would result in the following approximate weights of each constituent:

TABLE-US-00002 Creatine Di-Sodium phosphate 509 mg Alpha GPC 252 mg Blueberry powder extract 101 mg Trisodium citrate  60 mg Magnesium stearate  9 mg Total 930 mg

[0047] Of course, in manufacturing such capsules, a single capsule run is not practicable. Assuming a single bottle of this supplement would contain 30 capsules, a 1000 bottle run preferably includes the following:

TABLE-US-00003 Creatine di-sodium phosphate 546.8 kg Alpha GPC 270.5 kg Blueberry powder extract 108.2 kg Trisodium citrate 64.55 kg Magnesium stearate as needed

[0048] Described more generally, the supplement can contain approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 250 mg of a 50% α-GPC (L-alpha-glycerylphosphorylcholine), approximately 100 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and approximately 60 mg of trisodium citrate. The supplement of the present invention is most preferably an admixture of dry ingredients, with the magnesium stearate, with the preferred amount of magnesium stearate in a single dose from 0 to 9 mg.

[0049] It is believed that quite possibly, substantial efficacy can be obtained with a half dosage. In this form, a single serving contains approximately 250 mg creatine active ingredient, approximately 125 mg α-GPC, approximately 50 mg total phenols and approximately 50 mg trisodium citrate. Given this total serving/daily dosage of active ingredients, the most preferred weight ratio of essential or active ingredients to each other in each serving is 10:5:2:2.

Example 2

[0050] In addition to the most preferred form, the supplement may also comprise approximately 325 mg creatine hydrochloride (of which approximately 78% by weight is the creatine active ingredient), approximately 250 mg of a 50% α-GPC, approximately 180 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and 60 mg trisodium citrate, with the magnesium stearate additive being preferred but optional. Most preferably, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 125 mg α-GPC, approximately 50 mg total phenols and approximately 50 mg trisodium citrate.

Example 3

[0051] Another form of the supplement of the present invention may contain approximately 285 mg creatine monohydrate, approximately 250 mg of a 50% α-GPC and approximately 180 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and 50 mg trisodium citrate with the magnesium stearate additive being preferred but optional. Accordingly, in the most preferred form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 125 mg α-GPC, approximately 30 mg total phenols and from 25-100 mg trisodium citrate.

Example 4

[0052] In another embodiment, the supplement contains approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 250 mg of a 50% α-GPC and approximately 55 mg of a green tea standardized to approximately >90% total phenols, together with 100 mg trisodium citrate, with a magnesium stearate additive being preferred but optional. Accordingly, in the most preferred form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 125 mg α-GPC, approximately 50 mg total phenols, and from 25-100 mg trisodium citrate.

Example 5

[0053] In yet another embodiment, a supplement contains approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 250 mg of a 50% α-GPC and approximately 55 mg of a grape seed extract (GSE) standardized to approximately 95% total phenols, and from 10-50 mg trisodium citrate, with the magnesium stearate additive being preferred but optional. Accordingly, in this form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 125 mg α-GPC, from approximately 10-50 mg total phenols and from 25-100 mg trisodium citrate.

Example 6

[0054] In another formulation, the supplement of the present invention contains approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 150 mg of phosphatidyl choline (PC), approximately 50-180 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and 30-60 mg trisodium citrate plus optionally magnesium stearate. Accordingly, in the most preferred form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 150 mg PC, approximately 30-60 mg total phenols and from 25-100 mg trisodium citrate.

Example 7

[0055] Alternatively, a supplement the present invention contains approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 150 mg of CDP (cytidine-diphosphate choline) and approximately 50-180 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and 30-60 mg trisodium citrate, with the magnesium stearate additive being preferred but optional. Accordingly, in the most preferred form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 150 mg CDP, approximately 50 mg total phenols and 25-100 mg trisodium citrate.

Example 8

[0056] In yet another embodiment, the supplement contains approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient), approximately 250 mg of a 50% α-GPC and approximately 100 mg of a turmeric extract standardized to approximately >95% total curcuminoids, together with 100 mg trisodium citrate, with a magnesium stearate additive of 0.5 mg to 10 mg being preferred but optional. Accordingly, in the most preferred form, a single serving (which also represents the most preferred total daily dosage) contains approximately 250 mg creatine, approximately 125 mg α-GPC, approximately 50 mg total phenols, and from 30-50 mg trisodium citrate. Alternatively, one could reduce the amount of the turmeric extract of which 95% curcumimoids to from less than 100 mg to 50 mg.

[0057] As indicated above, the formulations of the present invention significantly benefit from the addition of trisodium citrate. It is postulated that improvements in absorption and efficacy of the formulations of the supplements of the present invention when trisodium citrate is present may be at least partially attributed to a synergistic effect between the choline moiety (preferably derived from α-GPC) and the trisodium citrate. To evaluate this theory, the permeability of α-GPC was tested through a Caco2 monolayer in the presence and absence of trisodium citrate. Three mL of 10 mM L-α-GPC in Dulbecco's phosphate-buffered saline (known in the art as “DPBS”) alone or with 10 mM trisodium citrate was added to the donor chamber of each of 3 side-by-side diffusion cells with a confluent Caco2 monolayer there between (TEER˜900 Ohm*cm2). Samples were taken at 15 minute intervals for 90 minutes and replaced with fresh isotonic DPBS. Samples were taken from donor chamber at time 0 and at 90 minutes. This experiment consisted of two independent runs (runs 1 and 2). L-α-GPC was quantified using Sciex 3200 Qtrap LC/MS/MS in positive mode (257.9/104.2) using a 150 mM Phenomenex Synergi polar rp column with a mobile phase consisting of 25% methanol 75% water (v/v) with 0.1% formic acid and a flow of 0.5 ml/min.

[0058] Results from these runs were reported in terms of cumulative α-GPC measured in terms of μg/cm2 (y axis) against time in minutes (x axis). The data is summarized in Table 1 and is illustrated in FIG. 1.

TABLE-US-00004 TABLE 1 15 min 30 min 45 min 60 min 75 min 90 min α-GPC 84.11 199.54 310.52 454.48 574.64 720.21 α-GPC 59.11 438.47 499.12 552.54 620.45 721.50 α-GPC + 135.19 456.27 524.29 656.83 879.62 1351.3 trisodium citrate α-GPC + 68.35 645.13 909.07 1288.6 1689.7 2063.9 trisodium citrate

[0059] These studies show that the presence of trisodium citrate significantly increases the permeation of α-GPC through a Caco2 monolayer. As a total of 30 uM α-GPC was applied to the donor chamber approximately 10% of the total α-GPC permeated in the control and between 15 and 30% permeated in the presence of trisodium citrate.

[0060] When trisodium citrate is included in the formation, preferably the trisodium citrate represents from 2% to 10% of the total weight of the formulation, more preferably 2.5% to 7.5% or even 4% to 6% of the total weight of the formulation and most preferably 3% to 5% of the total weight of the formulation.

Example 9

[0061] In addition to the most preferred embodiment of the present invention, additional additives are present in other preferred embodiments of the present invention. Other preferred embodiments containing the α-GPO, disodium phosphocreatine and phenolic extract of Example 1, but also include one or more additives selected from the group consisting of polyethylene glycol (most preferably PEG 3350), Eudraguard, α-cyclodextrin and trisodium citrate.

Example 10

[0062] In a preferred supplement of the present invention, the supplement contains approximately 100 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols and either approximately 500 mg creatine phosphate disodium salt (of which approximately half by weight is the creatine active ingredient) or approximately 250 mg of a 50% α-GPC, together with from 20-100 mg trisodium citrate. In one of these formulations, a single serving contains approximately 50 mg total phenols and either approximately 250 mg creatine or approximately 125 mg α-GPC.

Example 11

[0063] In other forms of the supplement of the present invention the supplement contains from 100 to 750 mg of creatine phosphate disodium salt, from 50 mg to 500 mg of a 50% α-GPC, from 50 to 250 mg of a Vaccinium angustifolium fruit extract standardized to approximately 30% total phenols, and approximately 0 to 200 mg of trisodium citrate. It is believed that the amount of the trisodium citrate may be decreased in formulations such as these in that the creatine source may contribute significant sodium for the purpose of enhancing activity of the resulting combination.

Example 12

[0064] In addition to the most preferred embodiment of the present invention, additional additives are present in other preferred embodiments of the present invention. Other preferred embodiments containing the α-GPO, disodium phosphocreatine, phenolic extract and trisodium citrate of Example 1 (or alternatively other creatine derivative described herein) but also include one or more additives selected from the group consisting of polyethylene glycol (most preferably PEG 3350), Eudraguard, and alpha-cyclodextrin. Preferably, these additives do not constitute more than 2% of the essential or active ingredients or 0-20 mg of a single dose.

[0065] More generally, the preferred supplements of the present invention include one or more plant extracts enriched in polyphenols. Plant extracts are most preferably extracts selected from the group consisting of bilberries, blueberries, cranberries, chokeberries, strawberries, black currents, grapes, grape seeds, plums, sorghum, pinto beans, red beans, kidney beans, hazelnuts, pecans, pistachios, teas and cinnamon. Such extracts enriched in polyphenols may, in their simplest form, comprise juices in which the water content of is all, mostly or partially evaporated. More preferred plant extracts are processed in a way which includes multiple steps which may include one or more of the following steps: evaporation, filtration, centrifugation, column chromatography separation, liquid-liquid separation and size exclusion chromatography. In any case, the most preferred phenolic compounds include anthocyanins and/or proanthocyanins (type A and/or type B) and related phenolic compounds, as well one or more compounds selected from the group consisting of creatine (and/or creatine derivatives) and choline (including α-GPC). The creatine compounds in these supplements are most preferably creatine phosphate and salts.

[0066] The preferred choline in the supplements of the present invention comprise α-GPC. Trisodium citrate is also a most preferable additive and may be included in the supplements of the present invention.

[0067] The most preferred supplements of the present invention comprise a plant extract comprising a blueberry extract containing at least 30% total phenols, wherein a daily dosage of the supplement comprises 100-300 mg of 50% α-GPC, 300-750 mg of disodium phosphocreatine, and 100-250 mg of the blueberry extract. These supplements also may include 50-300 mg trisodium citrate.

[0068] In another series of experiments, the permeability of α-GPC through a Caco2 monolayer was measured to determine whether the presence of a blueberry-based polyphenol extract affected permeability. It was found that the presence of a blueberry polyphenol extract does not significantly change the permeation of α-GPC through a Caco2 monolayer. Additionally, it was determined that the presence of α-GPC did not significantly change the permeation for the blueberry polyphenols through the Caco2 monolayer.

[0069] More particularly, donor GPC concentrations were reduced to 5 mM. Three ml of 5 mM I-α-GPC in Dulbecco's phosphate-buffered saline (DPBS) alone or with 1 mg/ml blueberry polyphenol extract was added to donor chambers of each of 3 side by side diffusion cells with a confluent Caco2 monolayer between (TEER˜900 Ohm*cm2). Samples were taken at 15 minute intervals for 90 minutes and replaced with fresh isotonic DPBS. Samples were taken from donor chamber at time 0 and at 90 minutes. This experiment consisted of two independent runs (as identified below as run 1 and run 2). Alpha GPC was quantified using Sciex 3200 Qtrap LC/MS/MS in positive mode (257.9/104.2) using a 150 mM Phenomenex Synergi polar rp column with a mobile phase consisting of 25% methanol 75% water (v/v) with 0.1% formic acid and a flow of 0.5 ml/min. The data from the runs is summarized in Table 2, illustrated in FIG. 2 (Total Alpha GPC permeability through a Caco2 monolayer) and averaged below in Table 3. The averaged data is illustrated in FIG. 3. In each of the graphs, the vertical axis units are cumulative L-α-GPC in μg/cm2 and the horizontal axis units are minutes.

TABLE-US-00005 TABLE 2 15 min 30 min 45 min 60 min 75 min 90 min (1) αGPC 18.75 41.37 67.92 103.2 150.0 222.4 (2) αGPC 47.16 200.9 262.8 316.1 373.3 442.1 (1) αGPC + 50.76 104.0 168.3 207.5 247.3 286.4 blueberry (2) αGPC + 37.03 253.1 279.0 305.2 333.0 360.1 blueberry

TABLE-US-00006 TABLE 3 15 min 30 min 45 min 60 min 75 min 90 min αGPC 0.128 0.471 0.643 0.815 1.017 1.292 αGPC + 0.171 0.694 0.870 0.997 1.128 1.256 blueberry

[0070] It is noted that not all polyphenolic extracts are enhanced as effectively as the concentrated blueberry extract used in the preferred embodiments described herein. In experiments conducted to compare the effect of trisodium citrate on a blueberry extract and on a cranberry extract, tests conducted using the Caco2 monolayer as described above showed a modest improvement of the cranberry extract to which the trisodium citrate was added, but this effect was measurably less than the effect of the trisodium citrate on permeation blueberry extract. It is postulated that the enhancement effect may be unusually superior due to the unique polyphenol size distribution in the blueberry extract, in which there are significant numbers of smaller polyphenol molecules. Data was collected and averaged at 15, 30, 45, 60, 75 and 90 minutes, and is summarized in Table 4. FIG. 4 illustrates this data which taken as a whole, represents the cumulative polyphenol permeation through a Caco2 membrane. The vertical axis of FIG. 4 represents cumulative polyphenols in ug propyl galate equivalents. The horizontal axis represents time in minutes.

TABLE-US-00007 TABLE 4 Blueberry + Cranberry + Blueberry Trisodium Citrate Cranberry Trisodium Citrate 15 min 4.274 3.439 1.490 2.464 30 min 6.101 5.404 3.548 3.014 45 min 6.442 6.767 3.541 4.144 60 min 7.108 9.335 3.859 5.530 75 min 9.560 11.069 5.268 6.080 90 min 9.229 14.009 4.889 6.746

[0071] A preferred formulation of the supplement of the present invention containing 500 mg of disodium phophocreatine, 250 mg of α-glycerol phosphocholine, 200 mg of blueberry extract and 60 mg of trisodium citrate was provided as a single oral dose taken in the morning to volunteers. The volunteers spanned an age of 40 to late 80's in age, with an approximate median age of 60 years old. Two of the individuals were in their 80s and both suffered from age-related cognitive and physical decline with mild to moderate dementia. The elder man was taking required medical treatment for onset Alzheimer's disease. After the first two weeks of daily use, each volunteer exhibited remarkable improvement in daily cognitive function, i.e., alertness, conversational skills, problem solving, improvement in the daily routine for personal care, and improved physical activity. In particular, the two elderly volunteers exhibited marked improvement in the ability to be up and around, contributing to conversations, as well as daily dressing and self-care, which required substantially less time.

[0072] Accordingly, a method of promoting health in individual persons, includes the steps of administering the oral supplements to a human being is contemplated by formulations and combinations described herein, it being understood that certain combinations will prove optimum. Furthermore, it is also contemplated that oral administration of the oral supplements of the present invention may find utility when administered to other mammals such as dogs and cats, provided the amounts of the individual doses are adjusted appropriately.

[0073] Furthermore, depending upon the size/body mass/age of the individual taking the oral supplements of the present invention, fractional doses of these oral doses may be appropriate. So, for example, a half dose of any of the examples and ranges described above may be taken each day if desired. Also by way of example, two half doses or other fractional doses each day may be deemed appropriate if the size of the full dose described herein in the examples and ranges above if difficult for an individual to swallow.

[0074] In addition to dosage size variations of the examples and ranges described above, the inventors hereof believe that unexpected improvements in physical, cognitive, and other mental health may be achieved even in the absence of the trisodium citrate, although such improvements will be more modest than those achieved with the oral dietary supplement of the present invention comprising a plant extract enriched in polyphenols, a creatine derivative, a choline, and trisodium citrate. Accordingly, the invention described herein also contemplates an oral dietary supplement comprising a plant extract enriched in polyphenols, a creatine derivative and a choline. The relative weights and weight ranges of dosages for this aspect of the present invention are in the many combinations specified above, but omitting the trisodium citrate.

[0075] In summary, the oral dietary supplement of the present invention includes a plant extract enriched in polyphenols in which the plant extract enriched in polyphenols is extracted and selected from the group consisting of polyphenol-containing fruits, fibrous edibles, beans, nuts, spices, teas, vegetables, flowers and grasses and the polyphenols are selected from the group consisting of monomers, dimers, trimers, oligomers and polymers, together with a creatine derivative, a form of choline, and trisodium citrate.

[0076] Preferably the oral dietary supplements of the present invention includes polyphenols selected from the group consisting of anthocyanins, phenolic acids, lignans, flavonoids and proanthocyanins, the creatine derivative is selected from the group of creatine itself, creatine monohydrate, creatine salts, creatine esters, creatine phosphoryl esters and their salts, and creatine chelates, and the choline is a choline derivative selected from the group consisting of choline itself, choline salts, choline esters and choline phosphoryl esters.

[0077] The plants from which the plant extracts enriched in polyphenols are preferably extracted from one or more of the following: acai, aronia, bilberries, blueberries, cranberries, chokeberries, coffee berries, currants, red currents, black currents, black raspberries, elderberries, grapes, mangos, marionberries, peaches, pomegranate, plums, prunes, raspberries and strawberries, the fibrous edibles are selected from the group consisting of sorghum, radish, potato, rutabaga and turnip, the beans are selected from the group consisting of pinto beans, red beans and kidney beans, the nuts are selected from the group consisting of hazelnuts, pecans, pistachios, and walnuts, the spices are selected from the group consisting of cinnamon, curcumin, turmeric and pepper seeds, and the vegetables are selected from the group consisting of artichokes, asparagus, carrots, endives, olives, onions, spinach, shallots, red lettuce, and pepper.

[0078] Preferably, fruits are the source of the plant extracts used in the present and the preferred fruits acai, aronia, bilberries, blueberries, cranberries, chokeberries, coffee berries, black currants, black raspberries, elderberries, grapes, peaches, mangosteen, pomegranate, plums, prunes, raspberries and strawberries.

[0079] In the present invention, creatine itself and salts thereof may be used. Alternatively, creatine hydrochloride may be used. Also, α-GPC a preferred form of the choline used in formulations of the present invention. Furthermore, polyethylene glycol may also be incorporated in the formulations of the present invention.

Example 13

[0080] In order to more fully understand the effects of the formulations within the invention, an ad hoc clinical dosing evaluation was conducted over the course of several months in 24 human subjects. In this evaluation, three different formulation dosing levels were sampled and tried by the subjects for between 1 day and up to 30 days. The formulations were as follows:

TABLE-US-00008 Phospho- Blueberry Tri Sodium α-GPC Creatine Extract Citrate Low Dose  63 mg 250 mg  50 mg 30 mg Mid Dose 125 mg 500 mg 100 mg 60 mg High Dose 250 mg 500 mg 100 mg 60 mg

[0081] Most of the participants in this ad hoc study reported one or more of the following positive results (a) improvement in short-term memory, as reflected in staying on task without fewer lapses of memory, (b) improvement in long-term memory, (c) better sleep as described as more restful with fewer interruptions each night, (d) noticeable improvements in daily energy, allowing for the lessening the need of stimulants via coffee or tea with caffeine.

[0082] Not everyone experienced precisely the same effect, and some did not see much difference between the different doses consumed. For those consuming the highest dose there was a greater differential of effect, with some participants, after one or two of the higher doses, there was a noticeable mental over stimulation. Five of the participants reported no noticeable effects. For other participants, after a few weeks to a month with the higher doses, overstimulation started to occur and was reported by other observers in the household. This effect manifested itself as a noticeable irritability which is described as a “cholinergic” effect of too much choline in the central nervous system. One individual that had been previously consuming up to two grams a day of α-GPC noticed this effect and most treatment-naïve individuals noticed it immediately.

[0083] Most interestingly, two elderly individuals (male and female) showed a remarkable response at the high dose level overcoming bland or flat affect and lack of responsiveness characteristic of elderly aging dementia after dosing for a few days. Both individuals showed improvements in short and long term memory as well as in cognitive functions. When these two individuals ran out of the doses, they purchased commercially available market leading product, but did not notice any effect whatsoever. When re-supplied the original high dose the behavior of being enabled to respond and communicate returned. However, after some additional weeks of consumption, the irritability effects of consuming too much choline appeared.

[0084] From this ad hoc study, it was determined that acceptable dosing formations for the oral supplements of the present should contain α-GPO at a level of from 25 to 250 mg, disodium phosphocreatine at levels of from 50-500 mg, of an extract containing from 20% to 33% phenolic compounds, of from 25 to 250 mg, and of trisodium citrate from 20 to 50 mg. More preferably, the oral supplements of the present would contain α-GPC at a level of from 60 to 125 mg, disodium phosphocreatine at levels of from 50-500 mg, of an extract containing from 20% to 33% phenolic compounds, of from 50 to 100 mg, and of trisodium citrate from 30 to 60 mg. Most preferably, a dose of the oral dietary supplement of the present invention contains at least 25 mg of polyphenols.

[0085] In one preferred form, the oral dietary supplement the present invention comprises disodium phosphocreatine, the plant extract comprises a blueberry extract containing at least 30% total phenols, and a daily dosage of the supplement comprises from 100-350 mg of the α-GPC, 300-750 mg of the disodium phosphocreatine, 100-250 mg of blueberry extract and 0-300 mg trisodium citrate. This supplement and other formulations of the present invention are preferably taken in a form selected from the group consisting of encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules and beverages.

[0086] Alternatively, a daily dosage of the supplement comprises 250 mg of α-GPO, 500 mg of disodium phosphocreatine, 100 mg of a blueberry extract and 125 mg of the trisodium citrate, and would preferably be incorporated in encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules or beverages. Most preferably, the blueberry extract contains at least 30% total phenols.

[0087] In other embodiments of oral dietary supplement of the present invention, a daily dosage of the supplement contains from 25-350 mg of α-GPC, 100-750 mg of the disodium phosphocreatine, 25-250 mg of blueberry extract and 0-300 mg trisodium citrate. Preferably, the blueberry extract containing at least 30% total phenols and the supplement is in the form of encapsulated powders, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, gelatin capsules or beverages.

[0088] In a particular embodiment of the oral dietary supplement of the present invention, a daily dosage of the supplement comprises 63 mg of the α-GPC, 250 mg of the disodium phosphocreatine, 50 mg of the blueberry extract and 60 mg of the trisodium citrate. Most preferably, the blueberry extract contains least 30% total phenols.

[0089] In the most preferred formulations of the present invention, the plant extract enriched in polyphenols comprises a blueberry extract whose bioavailability is enhanced by the presence trisodium citrate. Similarly, the choline component comprises α-GPC whose bioavailability is also enhanced by the presence of the trisodium citrate. Furthermore, the creatine derivative which may comprise disodium phosphocreatine whose bioavailability is also enhanced by the presence of α-GPC, the blueberry extract and the trisodium citrate due to their respective and combined enhanced bioavailability effects.

[0090] The invention described herein also includes a method of promoting health of an individual person comprising providing the oral supplements of the present invention to individuals in the combinations described herein, such that improved mental and physical functions might be experienced.