CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/164,289, filed May 20, 2015, the teaching of which are hereby incorporated by reference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Folate (B ₉ ) is part of a healthy diet and is commonly found in green leafy vegetables, legumes, nuts, orange juice and some fruits. Folate (B ₉ ) is water-soluble, and the body requires it for cell growth and reproduction. The body must digest and process folic acid, synthetic B ₉ , before it can be used by the body. In fact, the body goes through several steps in order to "break down" folic acid and get the full benefit. As a result of these biochemical processes, the body makes L-methylfolate. The importance of L-methylfolate, unlike folic acid, is it can cross the blood brain barrier. It has been shown that many people have a MTHFR polymorphism that limits their body's ability to reduce folic acid into L- methylfolate. Other risk factors including certain medications, diseases, lifestyle habits, and age may also increase an individual's risk of having a less than optimal amount of this necessary chemical, L-methylfolate, in the brain.

[0003] Like B ₉ , there are other B vitamins that must be converted to their active forms in order for the body to utilize them. This includes vitamin B ₆ and vitamin B _i2 , which are converted into their active forms before they are used by the body's cells for such vital functions as DNA production, cell reproduction and homocysteine metabolism.

[0004] In view of the foregoing, there is a need in the art for new immediate release formulations that contain the active form of the B vitamin and are water soluble. The present invention satisfies this and other needs.

BRIEF SUMMARY OF THE INVENTION

[0005] In one embodiment, the present invention provides a composition, comprising, consisting essentially of, or consisting of: a complex comprising vitamin B ₉ and a terpine glycoside such as diterpene glycoside; and

a pharmaceutically acceptable excipient.

[0006] In another embodiment, the present invention provides a composition, comprising: a complex comprising vitamin B ₉ and a terpine glycoside such as a diterpene glycoside;

vitamin B ₆ ;

vitamin Bi ₂ ; and a pharmaceutically acceptable excipient. [0007] In still another embodiment, the present invention provides a composition, comprising: a complex comprising vitamin B ₉ and a terpine glycoside such as diterpene glycoside; vitamin B _i2 ;

N-acetyl-L-cysteine; and

a pharmaceutically acceptable excipient.

[0008] In still yet another embodiment, the present invention provides a composition comprising: vitamin B ₉ ;

vitamin B ₆ ;

a complex comprising vitamin B ₁₂ and a terpine glycoside such as a diterpene glycoside; and a pharmaceutically acceptable excipient.

[0009] In still yet another embodiment, the present invention provides a composition comprising: vitamin B ₉ ;

a complex comprising vitamin B _i2 and a terpine glycoside such as a diterpene glycoside;

N-acetyl-L-cysteine; and a pharmaceutically acceptable excipient.

[0010] These and other aspects, objects and advantages will become more apparent when read with the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

[0011] As used herein, the term "formulation" includes compositions containing a biologically active substance such as a vitamin together with a glycoside. The formulation can include one or more pharmaceutically acceptable excipients.

[0012] As used herein, the term "bioavailability" includes the extent to which a substance is absorbed into the bloodstream of a subject after administration of a pharmaceutical formulation, and the amount of the substance that reaches the general circulation of the subject.

[0013] As used herein, the terms "enhancing bioavailability" and "increasing bioavailability" include administering a substance, such as a vitamin, so as to raise the bioavailability of the substance above the level at which it would be normally available. Administering the substance can include formulating the substance so as to increase the bioavailability. The substance can be formulated to increase the bioavailability by any suitable amount. In general, the methods of the present invention lead to bioavailability increases of at least about 10%, as compared to administration via control methods. Bioavailability levels can be determined by any suitable method, including analysis of the drug in a blood, plasma, serum, or urine sample taken from a subject after administration. Bioavailability can be assessed, for example, by plotting the concentration of a substance in the circulation of a subject over time after administration. Bioavailability can be considered in terms of the maximum (peak) concentration of the substance in the blood after administration, as well as in terms of the time required for the concentration of the substance to reach the peak concentration. The "area under the curve" (AUC) of the concentration-vs.-time plot can be calculated and used to determine the total amount of the substance that is absorbed into the blood stream after administration of a single dose.

[0014] As used herein, the term "water-soluble vitamin" includes vitamin C or a B vitamin.

[0015] As used herein, the term "B vitamin" includes thiamine (vitamin Bi), riboflavin, niacin/nicotinic acid/nicotinamide (vitamin B ₃ ), folic acid, folinic acid, L-methylfolate, L-5 methylfolate (vitamin B ₉ ), pyridoxine/pyridoxal/pyridoxamine (vitamin B ₆ ), biotin (vitamin B ₇ ), pantothenic acid (vitamin B ₅ ), and vitamin Bi ₂ . [0016] As used herein, the term "vitamin B ₆ " includes pyridioxine, pyridoxal, pyridoxamine, and pharmaceutically acceptable salts thereof.

[0017] As used herein, the term "vitamin B ₉ " can include numerous forms. In a specific aspect, vitamin B ₉ may be included in the form of folic acid. In another aspect, vitamin B ₉ may be included one or more of the forms of folic acid, folacin, metafolin, folate and/or one or more natural isomers of folate including (6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof, 5-methyl-(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof, 5- formyl-(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof, 10-formyl-(6R)- tetrahydrofolic acid or a polyglutamyl derivative thereof, 5,10-methylene-(6R)- tetrahydrofolic acid or a polyglutamyl derivative thereof, 5,10-methenyl-(6R)-tetrahydrofolic acid or a polyglutamyl derivative thereof and 5-formimino-(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof and the salts and esters thereof. Vitamin B ₉ may be in the form of a folate or folate derivative thereof that is eventually converted to 5-methyl- tetrahydrofolic acid in the body and/or is absorbed into the bloodstream as 5-methyl- tetrahydrofolic acid. Folates, such as folic acid and folate, are eventually absorbed in the body and converted to L-5-methyl-tetrahydrofolic acid. In another embodiment, vitamin B ₉ may be in the form of a folate or folate derivative thereof that increases blood folate levels, thereby reducing homocysteine levels.

[0018] As used herein, the term "vitamin Bi ₂ " includes a cobalamin compound according to Formula I:

CO- [0019] For cobalamin compounds according to Formula I, the oxidation state of the cobalt atom is +1, +2, or +3 depending on the identity of the ligand R. R can be absent in the compounds of Formula I. When R is absent, the compound is referred to as cobalamin. Alternatively, R is selected from methyl, cyano, and 5'-deoxyadenosyl. When R is methyl, the compound is referred to as methylcobalamin. When R is cyano, the compound is referred to as cyanocobalamin. When R is 5'-deoxyadenosyl, the compound is referred to as 5'- deoxyadenosylcobalamin. Vitamin B _i2 can also refer to a mixture of the cobalamin compounds described herein. Vitamin B _i2 can also refer to pharmaceutically acceptable salts of the cobalamin compounds described herein. [0020] As used herein, the term "vitamin C" includes L-ascorbic acid, also known as (R)-3,4- dihydroxy-5-((S)-l,2-dihydroxyethyl)furan-2(5H)-one, and pharmaceutically acceptable salts thereof.

[0021] As used herein, the term "terpene" refers to an organic compound having one or more isoprene-derived subunits. Terpenes are generally synthesized chemically or biochemically from isoprene (2-methyl- 1,3 -butadiene having the formula CH ₂ C(CH ₃ )CHCH ₂ , i.e., C ₅ H ₈ ) and isoprene derivatives. A "monoterpene" is generally understood to contain two isoprene subunits and has a base molecular formula of C ₁₀ H ₁₆ . "Diterpenes" and "triterpenes" typically contain four and six isoprene subunits, respectively. Terpenes, including diterpenes and triterpenes, can contain isoprene subunits arranged in a linear or cyclic configuration. The linear or cyclic backbones can be substituted with one or more moieties including, but not limited to, hydroxy, oxo, and carboxy groups.

[0022] As used herein, the term "glycoside" includes a compound having one or more sugar moieties and a non-sugar moiety. The sugar moieties generally contain from 1 to 6 monosaccharide subunits having from 5 to 6 carbon atoms. Examples of typical

monosaccharide subunits include, but are not limited to, glucose, allose, altrose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, arabinose, lyxose, ribose, xylose, ribulose, and xylulose. The monosaccharide subunits can also be deoxy sugars, amino sugars, or sulfosugars. The monosaccharide subunits can be linked to each other in a number of configurations. For example, linkages can occur between the 1 -carbon (the anomeric carbon) and the 4-carbon of adjacent monosaccharide subunits (i.e., a 1-4 linkage), the 1 -carbon and the 3 -carbon of adjacent monosaccharide subunits (i.e., a 1-3 linkage), the 1 -carbon and the 6-carbon of adjacent monosaccharide subunits (i.e., a 1-6 linkage), or the 1- carbon and the 2-carbon of adjacent monosaccharide subunits (i.e., a 1-2 linkage). A monosaccharide subunit can be linked within a sugar moiety such that the anomeric carbon is in the a- or β-configuration. The sugar moieties can also include linkages between carbon atoms other than the 1-, 2-, 3-, 4-, and 6-carbons. The non-sugar moiety in a glycoside ("the aglycone") is typically connected to a sugar moiety via an ether linkage.

[0023] As used herein, the term "diterpene glycoside" includes glycosides as defined above, wherein the non-sugar moiety is a diterpene. Examples of diterpene glycosides include, but are not limited to, rebaudiosides, suaviosides, goshonosides, paniculosides, stevioside, and rubososide. A stevioside is preferred. [0024] As used herein, the term "triterpene glycoside" includes glycosides as defined above, wherein the non-sugar moiety is a triterpene. Examples of triterpene glycosides include, but are not limited to, abrusosides, cimiracemosides, lansiosides, leucospilotasides, frondoside A, eximisoside A, and quadranguloside.

[0025] As used herein, the term "stevioside" (CAS 57817-89-7) refers to (4α)-13-[(2-0-β-ϋ- glucopyranosyl-P-D-glucopyranosyl)oxy]kaur-16-en-18-oic acid β-D-glucopyranosyl ester having the structure:

[0026] As used herein, the term "rebaudioside A" (CAS 58543-16-1) refers to (4a)-13-[(2- 0-P-D-glucopyranosyl-3-0-P-Dglucopyranosyl-P-D-glucopyranosy l)-oxy]kaur-6-en-8-oic acid β-D-glucopyranosyl ester having the structure:

[0027] As used herein, the term "rebaudioside D" (CAS 63279-13-0) refers to (4α)-13-[(0-β- D-glucopyranosyl-(l→2)-0-[P-D-glucopyranosyl-(l→3)]-P-D- glucopyranosyl)oxy]kaur-16- en-18-oic acid 2-0-P-D-glucopyranosyl-P-D-glucopyranosyl ester having the structure:

[0028] As used herein, the term "L-methylfolate" includes the compound (25)-2-[[4-[(2- amino-5-methyl-4-oxo-l,6,7,8-tetrahydropteridin-6- yl)methylamino]benzoyl]amino]pentanedioic acid, having the CAS number 134-35-0, and pharmaceutically acceptable salts thereof. [0029] As used herein, the term "N-acetylcysteine" includes the amino acid having the structure:

and pharmaceutically acceptable salts thereof. II. EMBODIMENTS [0030] In one embodiment, the present invention provides a composition, comprising: a complex comprising vitamin B ₉ and a terpine glycoside such as a diterpene glycoside; and

a pharmaceutically acceptable excipient.

[0031] In one embodiment, vitamin B ₉ is L-5-methyl-tetrahydrofolate or a salt thereof.

Suitable salts include, but are not limited to, calcium, magnesium, iron and the like. In certain preferred aspects, the vitamin B ₉ salt is a calcium salt of L-5-methyl-tetrahydrofolate.

[0032] In certain aspects, the composition comprises one or more excipients. Suitable excipients include microcrystalline cellulose, silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate and magnesium stearate.

[0033] Other pharmaceutical excipients may be included such as diluents, binders, lubricants (i.e. dibasic calcium phosphate, calcium carbonate, crospovidone, polyethylene glycol, methyl or ethylcellulose, or calcium stearate strength. Other excipients can include immediate release excipients.

[0034] In certain aspects, excipients can comprise between 15% to 40% w/w of the formulation or composition. In certain aspects, silicified microcrystalline cellulose comprises about 10% to about 30% such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% w/w of the composition.

[0035] In certain aspects, magnesium stearate comprises less than 1% of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w.

[0036] In certain aspects, the diterpene glycoside is stevioside.

[0037] In certain aspects, the B ₉ formulation has a ratio of vitamin B ₉ : to the glycoside of 1 : 1 w/wto 1:40 w/w, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, or 1:40 w/w.

[0038] In certain aspects, the nanoparticles comprise 50-90% w/w of the composition. In certain aspects, the nanoparticles comprise 50, 55, 60, 65, 70, 75, 80, 85 or 90 % w/w of the composition.

[0039] In certain aspects, the formulation has a ratio of vitamin B ₉ : to the glycoside of 1 : 15 w/wto 1:30 w/w.

[0040] In certain aspects, vitamin B ₉ and the glycoside form a nanoparticle that is about 0.1 nm to about 50 nm in diameter, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nm.

[0041] In certain aspects, the amount of B ₉ within the complex is about 1 mg to about 30 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg, including amounts in between. In certain aspects, the amount of B ₉ complex within the complex is about 3 mg to about 15 mg such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg.

[0042] In certain aspects, the formulation is in the form selected from the group consisting of a capsule, a tablet, a softgel, a powder, an effervescent form, a lozenge, other buccal formulations, or a solution suspension. Those of skill in the art will know of other forms for immediate release formulations.

[0043] In certain aspects, the oral composition is an immediate release oral product such as a tablet or capsule, and is formulated to release the active vitamin immediately after oral administration. With immediate-release, there is relatively rapid absorption of vitamin and an onset of accompanying pharmacodynamic effects.

[0044] In certain aspects, the composition further comprises docosahexaenoic acid (DHA). Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, sperm, testicles and retina. DHA is commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus

Schizochytrium.

[0045] In certain aspects, the formulation is useful as a medical food as delivering 7.5 mg or 15 mg of L-5-methyl-tetrahydrofolate comprising nanop articles, which is taken once, twice, thrice or four times daily. In certain instances, the formulation is taken with or without food and is taken at or about the same time every day. The composition is useful in the treatment of depression and other related depressive disorders.

[0046] In certain aspects, the composition is a medical food, wherein the components have GRAS status (Generally Recognized as Safe) as designated by the FDA or independent review and complies with general food safety and manufacturing standards.

[0047] In another embodiment, the present invention provides a composition, comprising: a complex comprising vitamin B ₉ and a terpine glycoside such as a diterpene glycoside; vitamin B ₆ ;

vitamin Bi ₂ ; and

a pharmaceutically acceptable excipient.

[0048] In certain aspects, the vitamin B ₉ is L-5-methyl-tetrahydrofolate or a salt thereof. In certain aspects, the vitamin B ₉ is a calcium salt of L-5-methyl-tetrahydrofolate.

[0049] In certain aspects, the formulation has a ratio of vitamin B ₉ : to the glycoside of 1 : 1 w/wto 1:40 w/w, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, or 1:40 w/w. In certain aspects, the formulation has a ratio of vitamin B ₉ : to the glycoside of 1:15 w/w to l:30w/w. The complex is a nanoparticle.

[0050] In certain aspects, the nanoparticles comprise 10-30% w/w of the composition. In certain aspects, the nanoparticles comprise 10, 15, 20, 25, or 30 % w/w of the composition.

[0051] In certain aspects, vitamin B ₉ and the glycoside form a nanoparticle that is about 0.1 nm to about 50 nm in diameter, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nm. In certain aspects, the vitamin B ₉ and the glycoside form a nanoparticle that is about 0.1 nm to about 10 nm in diameter.

[0052] In certain aspects, the amount of B ₉ within the complex is about 1 mg to about 30 mg such as 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,21,22,23,24,25, 26, 27, 28, 29, or 30 mg, including amounts in between.

[0053] In certain aspects, the excipient comprises one or more of a member selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate and magnesium stearate. [0054] Other pharmaceutical excipients may be included such as diluents, binders, lubricants (i.e. dibasic calcium phosphate, calcium carbonate, crospovidone, polyethylene glycol, methyl or ethylcellulose, or calcium stearate strength. Other excipients can include immediate release excipients.

[0055] In certain aspects, excipients can comprise between 35% to 80% w/w of the formulation or composition. In certain aspects, silicified microcrystalline cellulose comprises about 50% to about 70% such as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% w/w of the composition.

[0056] In certain aspects, magnesium stearate comprises less than 1% of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w. [0057] In certain aspects, the diterpene glycoside is stevioside. Those of skill in the art will know of other immediate release excipients.

[0058] In certain aspects, the amount of B ₆ (pyridoxal phosphate) is about 10 mg to about 60 mg such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mg.

[0059] In certain aspects, the amount of B ₆ (pyridoxal phosphate) is about 10% to about 30%w/w of the composition. For example, the amount of B ₆ is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% w/w.

[0060] In certain aspects, the amount of B _i2 is about 1 mg to about 10 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

[0061] In certain aspects, B _i2 comprises less than 1% or about 1% of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w.

[0062] In certain aspects, a single capsule contains 3 mg of L-methylfolate calcium in a nanoparticle, 35 mg of pyridoxal 5 '-phosphate (B ₆ ), and 2 mg of methylcobalamin, which capsule is taken once, twice, thrice or four times daily.

[0063] In certain aspects, the composition further comprises docosahexaenoic acid (DHA). Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, sperm, testicles and retina. DHA is commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus

Schizochytrium.

[0064] In certain aspects, the formulation is in the form selected from the group consisting of a capsule, a tablet, a softgel, a powder, a sachet, a stick pack, an effervescent form, or a lozenge.

[0065] In certain aspects, the oral composition is an immediate release oral products such as a tablet or capsule, and is formulated to release the active vitamin immediately after oral administration. With immediate-release, there is relatively rapid vitamin absorption and onset of accompanying pharmacodynamic effects.

[0066] In certain aspects, the composition is a medical food, wherein the components have GRAS status (Generally Recognized as Safe) as designated by the FDA or independent review and complies with general food safety and manufacturing standards.

[0067] In certain instances, the formulation is useful in the treatment of diabetic peripheral neuropathy (DPN). Diabetic neuropathy affects an individual's ability to feel sensation in different parts of the body, and especially feet and toes. The present invention provides a therapeutic formulation for the treatment of DPN. [0068] In still another embodiment, the present invention provides a composition, comprising: a complex comprising vitamin B ₉ and a terpine glycoside such as diterpene glycoside; vitamin Bi ₂ ;

N-acetyl-L-cysteine; and

a pharmaceutically acceptable excipient.

[0069] In certain aspects, vitamin B ₉ is L-5-methyl-tetrahydrofolate or a salt thereof. In certain aspects, wherein the vitamin B ₉ is a calcium salt of L-5-methyl-tetrahydrofolate.

[0070] In certain aspects, the excipient comprises one or more of a member selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate and magnesium stearate.

[0071] In certain aspects, excipients can comprise between 15% to 50% w/w of the formulation or composition. In certain aspects, silicified microcrystalline cellulose comprises about 20% to about 40% such as 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% w/w of the composition. [0072] Other pharmaceutical excipients may be included such as diluents, binders, lubricants (i.e. dibasic calcium phosphate, calcium carbonate, crospovidone, polyethylene glycol, methyl or ethylcellulose, or calcium stearate strength. Other excipients can include immediate release excipients.

[0073] In certain aspects, magnesium stearate comprises less than 1% of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w. [0074] In certain aspects, the composition further comprises croscarmellose sodium.

[0075] In certain aspects, the diterpene glycoside is stevioside.

[0076] In certain aspects, formulation has a ratio of vitamin B ₉ : to the glycoside of 1 : 1 w/w to 1:40 w/w, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, or 1:40 w/w. In certain aspects, the formulation has a ratio of vitamin B ₉ : to the glycoside of 1 : 15 w/w to 1 :30 w/w.

[0077] In certain aspects, vitamin B ₉ and the glycoside form a nanoparticle that is about 0.1 nm to about 50 nm in diameter, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 143, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nm. In certain aspects, the vitamin B ₉ and said glycoside form a nanoparticle that is about 0.1 nm to about 10 nm in diameter.

[0078] In certain aspects, the amount of B ₉ complex within the complex is about 1 mg to about 30 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg, including amounts in between. In certain aspects, the amount of B ₉ is about 5 mg to about 30 mg.

[0079] In certain aspects, the amount of B ₉ in the formulation is about 5% w/w to about 15% w/w such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% w/w.

[0080] In certain aspects, the amount of B _i2 is about 1 mg to about 30 mg. In certain aspects, the amount of B _i2 is about 1 mg to about 10 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

[0081] In certain aspects, B _i2 comprises less than 1% or about 1% of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w.

[0082] In certain aspects, the amount of N-acetyl-L-cysteine is about 100 mg to about 1 g such as 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 mg. [0083] In certain aspects, N-acetyl -L-cysteine can comprise between 40% to 70% w/w of the formulation or composition. For Example, NAC can be about 40, 4, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70%) w/w of the composition.

[0084] In certain aspects, the composition further comprises docosahexaenoic acid (DHA). Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, sperm, testicles and retina. DHA is commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus

Schizochytrium.

[0085] In certain aspects, the formulation is in the form selected from the group consisting of a capsule, a tablet, a softgel, a powder, a sachet, a stick pack, an effervescent form, or a lozenge.

[0086] In certain aspects, the oral composition is an immediate release oral products such as a tablet or capsule, and is formulated to release the active vitamin immediately after oral administration. With immediate-release, there is a relatively rapid vitamin absorption and onset of accompanying pharmacodynamic effects.

[0087] In certain aspects, a capsule comprises 5.6 mg of L-methylfolate, 2 mg of

methylcobalamin and 600 mg of N-acetylcysteine 600 mg.

[0088] In certain aspects, the composition is a medical food, wherein the components have GRAS status (Generally Recognized as Safe) as designated by the FDA or independent review and also complies with general food safety and manufacturing standards.

[0089] In still yet another embodiment, the present invention provides a composition comprising: vitamin B ₉ ;

vitamin B ₆ ;

a complex comprising vitamin B _i2 and a terpine glycoside such as a diterpene glycoside; and a pharmaceutically acceptable excipient.

[0090] In certain aspects, the vitamin B ₉ is L-5-methyl-tetrahydrofolate or a salt thereof. In certain aspects, the vitamin B ₉ is a calcium salt of L-5-methyl-tetrahydrofolate.

[0091] In certain aspects, the amount of B ₉ complex within the complex is about 1 mg to about 30 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg, including amounts in between.

[0092] In certain aspects, vitamin B ₉ is about 0.1-5% w/w of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1, 2, 3, 4, or 5% w/w. [0093] In certain aspects, the excipient comprises one or more of a member selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate and magnesium stearate.

[0094] Other pharmaceutical excipients may be included such as diluents, binders, lubricants (i.e. dibasic calcium phosphate, calcium carbonate, crospovidone, polyethylene glycol, methyl or ethylcellulose, or calcium stearate strength. Other excipients can include immediate release excipients.

[0095] In certain aspects, silicified microcrystalline cellulose comprises about 50% to about 70% such as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70%) w/w of the composition.

[0096] In certain aspects, magnesium stearate comprises less than 1%> of the composition such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or about 1% w/w.

[0097] In certain aspects, the diterpene glycoside is stevioside. Those of skill in the art will know of other immediate release excipients. [0098] In certain aspects, the amount of B ₆ is about 10 mg to about 60 mg such as 10, 11,12, 143, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mg.

[0099] In certain aspects, the amount of B ₆ (pyridoxal phosphate) is about 10%> to about 30%> w/w of the composition. For example, the amount of B ₆ is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% w/w.

[0100] In certain aspects, the amount of B _i2 is about 1 mg to about 30 mg. In certain aspects, the amount of B _i2 is about 1 mg to about 10 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

[0101] In certain aspects, formulation has a ratio of vitamin B _i2 : to the glycoside of 1 : 1 w/w to 1:40 w/w, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, or 1:40 w/w. In certain aspects, the formulation has a ratio of vitamin B _i2 : to the glycoside of 1 : 15 w/w to 1 :30 w/w. The B glycoside complex forms a nanoparticle. The nanoparticles comprise about 10% to about 30% of the composition. For example, the composition comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30% w/w.

[0102] In still yet another embodiment, the present invention provides a composition comprising: vitamin B ₉ ;

a complex comprising vitamin Bi ₂ and a terpine glycoside such as a diterpene glycoside;

N-acetyl-L-cysteine; and

a pharmaceutically acceptable excipient.

[0103] In certain aspects, the vitamin B ₉ is L-5-methyl-tetrahydrofolate or a salt thereof. In certain aspects, the vitamin B ₉ is a calcium salt of L-5-methyl-tetrahydrofolate.

[0104] In certain aspects, the excipient comprises one or more of a member selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate and magnesium stearate.

[0105] Other pharmaceutical excipients may be included such as diluents, binders, lubricants (i.e. dibasic calcium phosphate, calcium carbonate, crospovidone, polyethylene glycol, methyl or ethylcellulose, or calcium stearate strength. Other excipients can include immediate release excipients. [0106] In certain aspects, the diterpene glycoside is stevioside. Those of skill in the art will know of other immediate release excipients.

[0107] In certain aspects, the amount of B ₉ is about 1 mg to about 20 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. In certain aspects, the amount of B6 is about 0.1% to about 5% of the composition. [0108] In certain aspects, the amount of N-acetyl-L-cysteine is about 100 mg to about 1 g such as 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 mg.

[0109] In certain aspects, N-acetyl -L-cysteine can comprise between 40% to 70% w/w of the formulation or composition. For Example, NAC can be about 40, 4, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70%) w/w of the composition. [0110] In certain aspects, the amount of Bi ₂ is about 1 mg to about 20 mg. In certain aspects, the amount of B _i2 is about 1 mg to about 10 mg such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

[0111] In certain aspects, formulation has a ratio of vitamin B _i2 : to the glycoside of 1 : 1 w/w to 1 :40 w/w, such as 1 : 1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, 1 : 11, 1 : 12, 1 : 13, 1 : 14, 1 : 15, 1 : 16, 1 : 17, 1 : 18, 1 : 19, 1 :20, 1 :21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, or 1 :40 w/w. In certain aspects, the formulation has a ratio of vitamin B _i2 : to the glycoside of 1 : 15 w/w to 1 :30 w/w.

The Bi ₂ glycoside complex forms a nanoparticle. The nanoparticles comprise about 1% to about 10% of the composition. For example, the composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% w/w.

[0112] In certain aspects, the formulations herein comprise a terpine glycoside, which is a diterpine glycoside. Stevioside ("stevia") is a diterpene glycoside that is isolated from the Stevia leaf (Stevia rebaudiana; Asteraceae). Stevioside has a molecular formula C3 ₈ H ₆ oOi ₈ and a molecular weight of 804. In pure form, it is a crystal or white powder. Another diterpene glycoside that is isolated from the Stevia leaf is rebaudioside, which exists in several forms, including rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, and rebaudioside F.

[0113] Another diterpene glycoside that is isolated from the Chinese sweet leaf tea (Rubus suavissimus; Rosaceae) and from stevia leaves (Stevia rebaudiana; Asteraceae) is steviol monoside. The structure of steviol monoside has only one glucose molecule rather than two as in rubusoside. Steviol monoside can be isolated from the sweet leaf tea, stevia leaves, or be obtained through the partial acid or alkaline hydrolysis of rubusoside to cleave one glucose molecule. Unlike rubusoside, steviol monoside is not a dominant diterpene glycoside in the sweet leaf tea or stevia plant. [0114] Other diterpenes that contain various numbers of glucose moieties are known. These compounds include: paniculoside IV, suaviosides A, B, Ci, Di, D ₂ , E, F, G, H, I, and J as identified by Ohtani et al. (1992, Phytochemistry 31(5): 1553-1559), and goshonosides Fi to F ₅ as identified by Seto et al. (1984, Phytochemistry 23 (12): 2829-2834). Although many diterpene glycosides such as stevioside, rebaudioside A, rubusoside, steviol monoside, and suavioside B, G, I, J, and H taste sweet, other diterpene glycosides are tasteless or bitter. For example, paniculoside IV is tasteless, suavioside Ci tastes bitter, suavioside Di is tasteless, suavioside D ₂ tastes bitter, suavioside E is tasteless, and suavioside F tastes bitter as indicated by Ohtani et al. (1992, Phytochemistry 31(5): 1553-1559).

[0115] Accordingly, some embodiments of the present invention provide a formulation for enhancing bioavailability as described above, wherein the glycoside is a diterpene glycoside. In some embodiments, the diterpene glycoside is selected from rubusoside, stevioside, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E,

rebaudioside F, steviol monoside, dulcoside A, steviol bioside, paniculoside, suavioside A, suavioside B, suavioside CI, suavioside Dl, suavioside D2, suavioside E, suavioside F, suavioside G, suavioside H, suavioside I, suavioside J, goshonoside F l, goshonoside F2, goshonoside F3, goshonoside F4, and goshonoside F5. In some embodiments, the diterpene glycoside is selected from stevioside, rebaudioside A, and rebaudioside D. In some embodiments, the diterpene glycoside is stevioside.

[0116] The present invention provides for the administration of compositions or formulations useful in the methods of the invention to a subject by immediate release. Such administration is selected when it is considered beneficial to achieve a certain level of the drug in a body compartment quickly (e.g., serum or plasma concentration).

[0117] The present invention includes any formulation known in the art that is suitable for administration of the formulations and compositions useful in the methods of the present invention. Examples include tablets, capsules such as gelatin capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like.

[0118] In certain aspects, the present compositions and formulations can take the form of solutions, liquids, gels, suspensions, emulsion, tablets, pills, pellets, capsules, liquids, powders, immediate-release formulations, suppositories, emulsions, aerosols, sprays, drops, suspensions, nanoemulsions, sublingual compositions, or any other form suitable for use. [0119] The compositions of the present invention may comprise flavorings (e.g., extract of ginger, mint, strawberry, vanilla, etc).

[0120] The compositions may be used in the form of their therapeutically acceptable salts and complexes, and also may be used alone or in appropriate association, as well as in

combination with other active compounds. [0121] The compositions and formulations described herein allow for the production of a "medical food" comprising the agent(s), vitamin(s), compound(s), or therapeutic(s) of the present invention for the improvement of a condition, disease, or disorder in a subject.

[0122] In some embodiments, the compositions and formulations of the present invention are the product of mixing the compounds in their wet or liquid forms, and subsequently preparing solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions.

[0123] In some embodiments, the compositions and formulations of the present invention are the product of mixing the compounds, vitamin(s) and drugs in their dry or solid forms.

[0124] In some embodiments, the compositions and formulations of the present invention are the product of mixing compounds, agents or drugs in their dry or solid forms and

subsequently encapsulating those compounds, agents and drugs in a capsule for oral administration. [0125] In some embodiments, the compositions and formulations of the present invention are the product of mixing compounds, vitamin(s), agents or drugs in their dry or solid forms and subsequently suspending those compounds, vitamin(s), agents or drugs in a suspension.

[0126] In some embodiments, the compositions and formulations of the present invention are the product of mixing compounds, agents, vitamin(s), or drugs in their dry or solid forms and subsequently preparing solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions.

[0127] In some embodiments, the compositions and formulations of the present invention are the product of mixing compounds, agents, vitamin(s), or drugs in their dry or solid forms, preparing tablets, pills, pellets, capsules, capsules, etc. and subsequently coating those compounds, agents and drugs with an enteric coating.

[0128] The compositions or formulations of the present invention can be mixed with suitable pharmaceutical carriers (vehicles) or excipients known to the art. Examples include water- soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids/semi- solids, cyclodextrins and phospholipids. They may also include gelatin, lactic acid, stearic acid or salts or complexes thereof, starch, milk, sugar, certain types of clay, including magnesium or calcium stearate, talc, oils, gums, vegetable fats, lipids, or and glycols.

[0129] Examples of acceptable salts useful in the invention include, but are not limited to, salts formed with inorganic acids (e.g., those selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or equivalent), or salts formed with acids or organic acids (e.g., acetic, oxalic, tartaric, succinic, malic, fumaric, aleic, ascorbic, benzoic acid, tannic, alginic, polyglutamic, naphthalene sulfonic acid, naphthalene disulfonic acid and polygalacturonic).

[0130] In some embodiments, one or more agents, compounds, or drugs of the present invention is mixed with omega 3 fatty acids, olive oil, or other source of lipid. In some aspects, one or more agents, compounds, or drugs of the present invention are conveyed to the body in conjunction with omega 3 fatty acids. In some aspects, one or more agents, compounds, or drugs of the present invention are conveyed to the body in conjunction with omega 3 fatty acids together in a capsule. [0131] The medicinal formulations of the compounds, agents and drugs of the present inventions may utilize conventional diluents, carriers, or excipients etc., known to the art.

[0132] In some embodiments, the compositions and formulations of the present invention may comprise a stabilizer, a surfactant, a nonionic surfactant, and may comprise a salt and/or a buffering agent. In aspects involving a stabilizer, the stabilizer may be any suitable stabilizer known to the art (e.g. Stella and Rajewski, 1997; Merisko-Liversidge and

Liversidge, 2003; U. S. Pat. No. 5,376,359). The stabilizer, may for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextran. The stabilizer may also be a sugar alcohol, such as mannitol or a combination the stabilizer types described above. In one embodiment, a stabilizer or stabilizers constitute approximately 0.1% to about 10% weight for weight of the compound.

[0133] To make the B ₉ glycoside complex, vitamin B ₉ is added to a reaction flask and a solvent (e.g. water) is added. The ratio of active ingredient to solvent (e.g. water) is about 1 : 1 to about 1 :500, or 1 : 100 to about 1 :500, or about 1 : 150 to about 1 :300 or 1 :250. Thereafter, the glycoside is added. The reaction mixture is heated to about 40 °C to about 100 °C, or about 50 °C to about 80 °C, or about 60 °C to about 80 °C. After heating from about 1 minute to about 60 minutes, vitamin B ₉ and glycoside admixture form a clear vitamin B ₉ admixture. Heating can be 1 minute, 5, 10, 15, 20, or 30 minutes. Removing the solvent (e.g., water) forms a dry powder. The water can be removed by lyophilization or spray drying. In certain aspects, high shear mixing can be used which allows for minimal or no external heating. The high shear speeds up dissolution. The shear mixing generates heat and promotes dissolution.

[0134] To make the B _i2 glycoside complex, vitamin B _i2 and a glycoside are admixed in a solvent. The solution is heated to form a clear vitamin B _i2 admixture; and the solvent is removed to form the formulation of vitamin Bi ₂ .

[0135] In certain instances, the complex comprising a vitamin and glycoside, such as a diterpene glycoside, makes the vitamin complex more water soluble than the vitamin without being in a complex. In certain instances, the vitamin complex becomes substantially more water soluble than the vitamin alone. In certain instances, the vitamin complex is 2, 3, 4, 5, 6, 7, 8, 9 or 10 times more water soluble than the vitamin per se. Alternatively, the vitamin is 5%-500% such as 10, 50, 75, 100, 200, 300, 400, or 500% more water soluble.

[0136] In certain embodiments, prior to the complexation, the active ingredient is soluble, freely soluble or very soluble in water. After complexation, the vitamin or active ingredient becomes more soluble. These terms are defined in the following table from Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, the latest edition.

METHODS OF USE

[0137] In one embodiment, the present invention provides a method for increasing the bioavailability a composition, comprising: administering a composition comprising a complex comprising vitamin B ₉ and a diterpene glycoside; and a pharmaceutically acceptable excipient, thereby increasing the bioavailability of vitamin B ₉ .

[0138] In another embodiment, the present invention provides a method for increasing the bioavailability a composition, comprising: administering a composition comprising a complex comprising vitamin B ₉ and a diterpene glycoside; vitamin B ₆ ; vitamin B _i2 ; and a pharmaceutically acceptable excipient thereby increasing the bioavailability of vitamin B ₉ . [0139] In still another embodiment, the present invention provides a method for increasing the bioavailability a composition, the method comprising: administering a composition comprising a complex comprising vitamin B ₉ and a diterpene glycoside; vitamin B _i2 ; N- acetyl-L-cysteine; and a pharmaceutically acceptable excipient, thereby increasing the bioavailability of vitamin B ₉ . [0140] In still yet another embodiment, the present invention provides a method for increasing the bioavailability of a composition, the method comprising: administering a composition comprising vitamin B ₉ ; vitamin B ₆ ; a complex comprising vitamin B _i2 and a terpene glycoside such as a diterpene glycoside; and a pharmaceutically acceptable excipient, thereby increasing the bioavailability of B _i2 . [0141] In still yet another embodiment, the present invention provides a method for increasing the bioavailability of a composition, the method comprising: administering a composition comprising vitamin B ₉ ; a complex comprising vitamin B _i2 and a terpene glycoside such as a diterpene glycoside; N-acetyl-L-cysteine; and a pharmaceutically acceptable excipient, thereby increasing the bioavailability of B _i2 .

III. EXAMPLES

Example 1

[0142] In this example, 15 mg of B ₉ formulated with a diterpene glycoside (e.g., stevia) in a 1 :20 ratio (300 mg) as nanoparticles are admixed with 100 mg of Prosolve SMCC 90 and capsule.

Table 1

Example 2

[0143] In this example, 3 mg of B ₉ formulated with 60 mg of a diterpine glycoside (e.g., stevia) in a 1 :20 ratio as nanoparticles are admixed with 35 mg of pyridoxal 5-phosphate. mg of methylcobalamin is added. 133 mg of Prosolv SMCC 90 is added and 1.5 mg of magnesium stearate. The formulation is thereafter tableted or placed in a capsule.

Table 2

Example 3

[0144] In this example, 6 mg of B ₉ formulated with 120 mg of a diterpine glycoside (e.g., stevia) in a 1 :20 ratio is admixed with 2 mg of methylcobalamine. 600 mg of N-acetyl-L- cysteine is added. 385 mg of Prosolv SMCC 50 is added and 8 mg of magnesium stearate 12 mg of croscarmellose sodium is also added. The formulation is thereafter tableted or placed in a capsule.

Table 3

Example 4

[0145] In this example, 3 mg of B ₉ is admixed with 35 mg of pyridoxal 5-phosphate. The admixture is mixed with 2 mg of methylcobalamine formulated in 52 mg of a diterpene glycoside (e.g. stevia) in a 1 :25 ratio as nanoparticles. 133 mg of Prosolv SMCC 90 is added and 1.5 mg of magnesium stearate. The formulation is thereafter tableted or placed in a capsule.

Table 4

Prosolv SMCC 90 133 174

Mg Stearate 1.5 1.5

Metafolin Total 275.15 tab or capsule wt.

Example 5

[0146] In this example, 6 mg of B ₉ formulated with 120 mg of a diterpine glycoside (e.g. stevia) in a 1 :20 ratio as nanoparticles, which are admixed with 2 mg of methylcobalamine. 600 mg of N-acetyl-L-cysteine is added. 385 mg of Prosolv SMCC 50 is added and 8 mg of magnesium stearate. 12 mg of croscarmellose sodium is also added. The formulation is thereafter tableted or placed in a capsule.

Table 5

[0147] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, one of skill in the art will appreciate that certain changes and modifications can be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.