WO2016185412A1 - Formulations à libération immédiate - Google Patents

Formulations à libération immédiate Download PDF

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Publication number
WO2016185412A1
WO2016185412A1 PCT/IB2016/052919 IB2016052919W WO2016185412A1 WO 2016185412 A1 WO2016185412 A1 WO 2016185412A1 IB 2016052919 W IB2016052919 W IB 2016052919W WO 2016185412 A1 WO2016185412 A1 WO 2016185412A1
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composition
vitamin
glycoside
complex
amount
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PCT/IB2016/052919
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English (en)
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Richard COPP
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Nestec S.A.
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Publication of WO2016185412A1 publication Critical patent/WO2016185412A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • A23L27/33—Artificial sweetening agents containing sugars or derivatives
    • A23L27/36—Terpene glycosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • 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.
  • B 9 there are other B vitamins that must be converted to their active forms in order for the body to utilize them.
  • 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
  • the present invention provides a composition, comprising: a complex comprising vitamin B 9 and a terpine glycoside such as a diterpene glycoside;
  • the present invention provides a composition, comprising: a complex comprising vitamin B 9 and a terpine glycoside such as diterpene glycoside; vitamin B i2 ;
  • the present invention provides a composition comprising: vitamin B 9 ;
  • a complex comprising vitamin B 12 and a terpine glycoside such as a diterpene glycoside; and a pharmaceutically acceptable excipient.
  • 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 N-acetyl-L-cysteine; and a pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • 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.
  • water-soluble vitamin includes vitamin C or a B vitamin.
  • 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 .
  • vitamin B 6 includes pyridioxine, pyridoxal, pyridoxamine, and pharmaceutically acceptable salts thereof.
  • vitamin B 9 can include numerous forms.
  • vitamin B 9 may be included in the form of folic acid.
  • 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, 5,10-methenyl-(6R)-
  • 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.
  • vitamin B 9 may be in the form of a folate or folate derivative thereof that increases blood folate levels, thereby reducing homocysteine levels.
  • vitamin Bi 2 includes a cobalamin compound 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.
  • R is selected from methyl, cyano, and 5'-deoxyadenosyl.
  • R is methyl
  • the compound is referred to as methylcobalamin.
  • R is cyano
  • the compound is referred to as cyanocobalamin.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ -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.
  • the term "diterpene glycoside” includes glycosides as defined above, wherein the non-sugar moiety is a diterpene.
  • diterpene glycosides include, but are not limited to, rebaudiosides, suaviosides, goshonosides, paniculosides, stevioside, and rubososide. A stevioside is preferred.
  • triterpene glycoside includes glycosides as defined above, wherein the non-sugar moiety is a triterpene.
  • triterpene glycosides include, but are not limited to, abrusosides, cimiracemosides, lansiosides, leucospilotasides, frondoside A, eximisoside A, and quadranguloside.
  • stevioside refers to (4 ⁇ )-13-[(2-0- ⁇ - ⁇ - glucopyranosyl-P-D-glucopyranosyl)oxy]kaur-16-en-18-oic acid ⁇ -D-glucopyranosyl ester having the structure:
  • the term "rebaudioside A” (CAS 58543-16-1) refers to (4a)-13-[(2- 0-P-D-glucopyranosyl-3-0-P-Dglucopyranosyl-P-D-glucopyranosyl)-oxy]kaur-6-en-8-oic acid ⁇ -D-glucopyranosyl ester having the structure:
  • the term "rebaudioside D” (CAS 63279-13-0) refers to (4 ⁇ )-13-[(0- ⁇ - 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:
  • 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.
  • N-acetylcysteine includes the amino acid having the structure:
  • the present invention provides a composition, comprising: a complex comprising vitamin B 9 and a terpine glycoside such as a diterpene glycoside; and
  • 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.
  • the vitamin B 9 salt is a calcium salt of L-5-methyl-tetrahydrofolate.
  • 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.
  • 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.
  • 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.
  • excipients can comprise between 15% to 40% w/w of the formulation or composition.
  • 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.
  • 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.
  • the diterpene glycoside is stevioside.
  • 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.
  • 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.
  • the formulation has a ratio of vitamin B 9 : to the glycoside of 1 : 15 w/wto 1:30 w/w.
  • 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.
  • 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.
  • 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.
  • a capsule a tablet, a softgel, a powder, an effervescent form, a lozenge, other buccal formulations, or a solution suspension.
  • 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.
  • immediate-release there is relatively rapid absorption of vitamin and an onset of accompanying pharmacodynamic effects.
  • the composition further comprises docosahexaenoic acid (DHA).
  • 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
  • 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.
  • 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.
  • GRAS status Generally Recognized as Safe
  • 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 ;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the vitamin B 9 and the glycoside form a nanoparticle that is about 0.1 nm to about 10 nm in diameter.
  • 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.
  • 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.
  • 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.
  • excipients can comprise between 35% to 80% w/w of the formulation or composition.
  • 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.
  • 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.
  • the diterpene glycoside is stevioside. Those of skill in the art will know of other immediate release excipients.
  • the amount of B 6 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.
  • the amount of B 6 (pyridoxal phosphate) is about 10% to about 30%w/w of the composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition further comprises docosahexaenoic acid (DHA).
  • 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
  • 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.
  • 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.
  • immediate-release there is relatively rapid vitamin absorption and onset of accompanying pharmacodynamic effects.
  • 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.
  • GRAS status Generally Recognized as Safe
  • the formulation is useful in the treatment of diabetic peripheral neuropathy (DPN).
  • DPN diabetic peripheral neuropathy
  • 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.
  • the present invention provides a composition, comprising: a complex comprising vitamin B 9 and a terpine glycoside such as diterpene glycoside; vitamin Bi 2 ;
  • 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.
  • 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.
  • excipients can comprise between 15% to 50% w/w of the formulation or composition.
  • 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.
  • 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.
  • 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.
  • the composition further comprises croscarmellose sodium.
  • the diterpene glycoside is stevioside.
  • 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.
  • the formulation has a ratio of vitamin B 9 : to the glycoside of 1 : 15 w/w to 1 :30 w/w.
  • 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.
  • the vitamin B 9 and said glycoside form a nanoparticle that is about 0.1 nm to about 10 nm in diameter.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • N-acetyl -L-cysteine can comprise between 40% to 70% w/w of the formulation or composition.
  • 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.
  • the composition further comprises docosahexaenoic acid (DHA).
  • 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
  • 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.
  • 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.
  • immediate-release there is a relatively rapid vitamin absorption and onset of accompanying pharmacodynamic effects.
  • a capsule comprises 5.6 mg of L-methylfolate, 2 mg of
  • 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.
  • GRAS status Generally Recognized as Safe
  • 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; and a pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the diterpene glycoside is stevioside.
  • 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.
  • the amount of B 6 (pyridoxal phosphate) is about 10%> to about 30%> w/w of the composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • the diterpene glycoside is stevioside. Those of skill in the art will know of other immediate release excipients.
  • 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.
  • the amount of B6 is about 0.1% to about 5% of the composition.
  • 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.
  • N-acetyl -L-cysteine can comprise between 40% to 70% w/w of the formulation or composition.
  • 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.
  • the amount of Bi 2 is about 1 mg to about 20 mg.
  • 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.
  • 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.
  • the formulation has a ratio of vitamin B i2 : to the glycoside of 1 : 1 w/
  • the Bi 2 glycoside complex forms a nanoparticle.
  • the nanoparticles comprise about 1% to about 10% of the composition.
  • the composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% w/w.
  • the formulations herein comprise a terpine glycoside, which is a diterpine glycoside.
  • Stevioside 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.
  • steviol monoside 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.
  • rubusoside Unlike rubusoside, steviol monoside is not a dominant diterpene glycoside in the sweet leaf tea or stevia plant.
  • Other diterpenes that contain various numbers of glucose moieties are known.
  • 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).
  • some embodiments of the present invention provide a formulation for enhancing bioavailability as described above, wherein the glycoside is a diterpene glycoside.
  • the diterpene glycoside is selected from rubusoside, stevioside, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E,
  • the diterpene glycoside is selected from stevioside, rebaudioside A, and rebaudioside D. In some embodiments, the diterpene glycoside is stevioside.
  • 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).
  • 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.
  • 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.
  • the compositions of the present invention may comprise flavorings (e.g., extract of ginger, mint, strawberry, vanilla, etc).
  • 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
  • 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.
  • 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.
  • compositions and formulations of the present invention are the product of mixing the compounds, vitamin(s) and drugs in their dry or solid forms.
  • compositions and formulations of the present invention are the product of mixing compounds, agents or drugs in their dry or solid forms and
  • 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.
  • 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.
  • 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.
  • compositions or formulations of the present invention can be mixed with suitable pharmaceutical carriers (vehicles) or excipients known to the art.
  • suitable pharmaceutical carriers 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.
  • 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).
  • inorganic acids e.g., those selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or equivalent
  • acids or organic acids e.g., acetic, oxalic, tartaric, succinic, malic, fumaric, aleic, ascorbic, benzoic acid, tannic, al
  • 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.
  • 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.
  • the stabilizer may be any suitable stabilizer known to the art (e.g. Stella and Rajewski, 1997; Merisko-Liversidge and
  • 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.
  • a stabilizer or stabilizers constitute approximately 0.1% to about 10% weight for weight of the compound.
  • 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.
  • 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
  • the water can be removed by lyophilization or spray drying.
  • 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.
  • 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 .
  • 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.
  • the vitamin complex becomes substantially more water soluble than the vitamin alone.
  • the vitamin complex is 2, 3, 4, 5, 6, 7, 8, 9 or 10 times more water soluble than the vitamin per se.
  • the vitamin is 5%-500% such as 10, 50, 75, 100, 200, 300, 400, or 500% more water soluble.
  • the active ingredient prior to the complexation, is soluble, freely soluble or very soluble in water. After complexation, the vitamin or active ingredient becomes more soluble.
  • 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 .
  • 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 .
  • 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 .
  • 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 .
  • 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 .
  • 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.
  • a diterpene glycoside e.g., stevia
  • 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.
  • 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.
  • B 9 3 mg 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.
  • 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.

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Abstract

La présente invention concerne des formulations à libération immédiate qui contiennent la forme active de vitamines B. L'invention concerne également des procédés d'augmentation de la biodisponibilité des vitamines.
PCT/IB2016/052919 2015-05-20 2016-05-18 Formulations à libération immédiate WO2016185412A1 (fr)

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WO2018237109A1 (fr) * 2017-06-23 2018-12-27 Yale University Nanomatériaux présentant une efficacité améliorée d'administration de médicament
US11478433B2 (en) 2017-06-23 2022-10-25 Yale University Nanomaterials with enhanced drug delivery efficiency

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