MULTIPLE FOLATE FORMULATION AND USE THEREOF

Abstract

A multiple folate composition comprising the following three different forms of folate: a folic acid (a salt or ester thereof); a folinic acid (a salt or ester thereof); and a 5-methyl-tetrahydrofolicacid (a salt or ester thereof) and other non-folate ingredients. The composition is useful as a nutritional supplement or medication in the treatment of a folate deficiency and sequella thereof and/or in conditions responsive to administration of a metabolically useful folate. The compositions are particularly of use in patients who have impaired or reduced ability to convert folic acid to its metabolically active forms and in the treatment of depression, particularly in pregnant women or women who may become pregnant.

Claims

1. A folate composition, operatively present in a dietary supplement with other non-folate substances, comprises the following three types of folate and no other folates: a folic acid, a folinic acid, and a 5-methyl-tetrahydrofolic acid, each of these three types of folate acids being present in the folate composition as a pharmaceutically acceptable salt, ester or mixtures of salt and esters.

2. The folate composition of claim 1, wherein one of the other non-folate substances comprises an adenosylcobalamine in the form of a pharmaceutically acceptable salt, ester or amide.

3. The folate composition of claim 2, wherein the amount of the adenosylcobolamine salt, ester or amide is from 20 micrograms to 2.5 milligrams.

4. The folate composition of claim 1, wherein one of the other non-folates comprises a pyridoxyl-5′-phosphate.

5. The folate composition of claim 1, wherein the types of folate consist of: between 0.1 mg and 1 mg of the folic acid, between 0.9 mg and 3.9 mg of the folinic acid, and between 1 mg and 14 mg of the 5-methyl-tetrahydrofolic acid.

6. The folate composition of claim 5, wherein the folic acid is of a pteroylmonoglutamic acid.

7. The folate composition of claim 5, wherein the folinic acid is of a pure 6S isomer 6S-5-LevoFormylFolic acid.

8. The folate composition of claim 5, wherein the 5-methyl-tetrahydrofolic is of a 6S-5-LevoMeFolic acid.

9. The folate composition of claim 5, further comprising a phospholipid from one of the omega-3 fatty acids.

10. The folate composition of claim 9, wherein the phospholipid is selected from the group of phospholipids consisting of DHA, EPA and ARA/AA.

11. The folate composition of claim 9, wherein the phospholipid is selected from the group of conjugated phospholipids moieties consisting of phosphatidylserine, phosphatidylethanolamines, and phosphatidylcholines.

12. The folate composition of claim 11, wherein the phospholipid is a phosphatidylcholine from eggs.

13. A dietary supplement comprising three forms of folate and other non-folates, the folates consisting of a folic acid, in the form of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof; wherein the amount of folic acid is at least 400 mcg, a folinic acid in the form of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof; wherein the amount of folinic acid is at least 400 mcg, and a 5-methyl-tetrahydrofolic acid, in the form of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof; wherein the amount of 5-methyl-tetrahydrofolic acid is at least 400 mcg; and the non-folates comprise an adenosylcobalamin or a pharmaceutically acceptable salt, ester, or amide, thereof, wherein the amount of adenosylcobalamin is between about 20 mcg and 2 mg.

14. The dietary supplement of claim 13, wherein the non-folates further comprise a pyridoxal 5′ phosphate.

15. A method of treating a patient in need of metabolically useful folate supplementation comprising administering to a pregnant woman, or to a woman who may become pregnant, the composition of claim 13.

16. The method of claim 14, wherein said patient is suffering from depression.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1 shows the metabolic relationship of folic acid and its normal human metabolic products.

[0040] FIG. 2 shows the remethylation and transsulfuration pathways and the interplay of homocysteine and folate.

[0041] FIGS. 3A and 3B show typical serotonin biosynthesis.

[0042] FIGS. 4A and 4B show typical dopamine biosynthesis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0043] For example, a folate-B12 composition comprises at least 3 forms of folate in combination with a vitamin B12 component. The 3 forms of folate required are selected from the group comprising:

[0044] a. at least one of folic acid (aka pteroylmonoglutamic acid), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof;

[0045] b. at least one of a folinic acid (aka formyltetrahydrofolate, aka formylTHF) comprising at least a 5-formyl-tetrahydrofolic acid (preferable a diasterioisomerically enriched (6S) form of 5-formyl-tetrahydofolic acid, most preferably a diasteriomerically pure (6S) form of 5-formyl-tetrahydofolic acid), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof; and

[0046] c. at least one of a 5-methyl-tetrahydrofolic acid (aka 1-methylfolate, aka MeTHF, aka MTHF) (preferably comprising at least a diastereoisomerically enriched 1-methyl-folate most preferably a diasteriomerically pure 1-methyl-folate (aka 1-5-methyl tetrahydrofolic acid)), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and mixtures thereof.

[0047] When used in the present invention, “diasteriomerically pure” is intended to mean at least the referenced material is 98% of the intended isomer, preferably at least 98.5%, more preferably at least 99%, still more preferably at least 99.5%, even more preferably at least 99.9% of the intended isomer. In a preferred embodiment of the invention at least one of said three forms of folate is present as a sugar amine conjugate (such as, without limitation, but preferably, glucosaminyl or galactosaminyl conjugated form thereof, more preferably a D-glucosaminyl or D-galactosaminyl conjugated form thereof). When desired, additional forms of folate may also be present, such as, without limitation, dihydrofolic acid, 5,10- methylene-tetrahydrofolic acid, and/or a tetrahydrofolic acid (other than the foregoing).

[0048] The present invention contains three different forms of folate, 1-methylfolate, folinic acid, and folic acid, to increase folate availability as a means to enhance homocysteine degradation. L-methylfolate is the metabolically active form of folate, readily available to participate in homocysteine remethylation reactions. It, unlike folic acid, does not require reduction by MTHFR-dependent process, and is therefore particularly indicated in the presence of a MTHFR polymorphism, such as C677T.

[0049] Folinic acid, also known as 5-formyltetrahydro-folate or leucovorin, is a derivative of tetrahydrofolic acid. Widely accepted as a folate rescue strategy to counter methotrexate toxicity in cancer treatment, its reduced folate properties lend itself to folate supplementation, particularly in the presence of dihydrofolate reductase inhibitors, such as pyrimethamine and methotrexate. It is also indicated for patients with certain genotypes of the dihydrofolate reductase enzyme that disturbs the reduction of dihydrofolate to tetrahydrofolate.

[0050] Folic acid administration has been shown to lower homocysteine in various populations (without the MTHFR polymorphism).

[0051] The vitamin B12 component is at least in the form of one or both of adenosylcobalamin or methylcobalamin, or pharmaceutically acceptable salts, esters, amides, or other metabolically useful prodrugs thereof, preferably in the form of adenosylcobalamin or methylcobalamin. In a preferred embodiment both an adenosylcobalamin (or a pharmaceutically acceptable salt, ester, amide, or other metabolically useful prodrug thereof and a methylcobalamin (or a pharmaceutically acceptable salt, ester, amide, or other metabolically useful prodrug thereof) are present. Methylcobalamin has the structure I below while adenosylcobalamin has the structure II below

##STR00001##

They each differ from cyano cobalamin in the replacement of the CN group (bound to the Co atom) of cyanocobalamin with methyl (methylcobalamine) or adenosyl (adenosylcobalamin), the methyl group and the adenosyl group being bound directly to the Co atom.

[0052] In general, the various required folates are present in independent amounts of up to 4 mg each, although they need not be present in equal amount preferably independently up to 3 mg of each, with a preferable minimum of at least 0.4 mcg. In some specific dosage forms preferred dosages include those where the three required forms of folate are present in equal weights. Other preferred dosage forms contain independently from 0.4 mcg up to 800 mcg of each of the three required forms. In other preferred dosage forms, each of the required three forms of folate is present independently in an amount of at least 2 mg and preferably (but not necessarily) each of these three forms is present in equal weights, in still other preferred dosage forms, each of the three required folate forms is independently present in a range in which the minimum and maximum (with the maximum being greater than the minimum) are selected from 0.4 mcg, 0.8 mcg, 1 mcg, 2 mcg, 5 mcg, 10 mcg, 20 mcg, 25 mcg, 50 mcg, 100 mcg, 200 mcg, 400 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1600 mcg, 2000 mcg, 2400 mcg, 2800 mcg, 3200 mcg, 3600 mcg, and 4000 mcg. In particular embodiments, each of the 3 required folates is independently present in an amount selected from 0.4 mcg, 0.8 mcg, 1 mcg, 2 mcg, 5 mcg, 10 mcg, 20 mcg, 25 mcg, 50 mcg, 100 mcg, 200 mcg, 400 mcg, 800 mcg, 1.000 mcg, 1200 mcg, 1600 mcg, 2000 mcg, 2400 mcg, 2800 mcg, 3200 mcg, 3600 mcg, and 4000 mcg, although dosage amounts intermediary between any of these specific amounts are also suitable where desired. It should be noted that the above amounts are calculated based on the uncomplexed, non-salt, non-ester folate form. Regardless of the form of the particular compounds, a highly preferred dosage form provides 3.83 mg 1-methylfolate, 2.4 mg 1-leucovorin, and 2.5 mg of folic acid.

[0053] The B12 component, whether adenosylcobolamin or methylcobolamin, are present in amounts which together are at least 10 mcg per dosage form up to 2000 mcg per dosage form, preferably at least 20 mcg. When a salt or ester or amide of these is used, the amount is an amount which provides the stated amount of the non-salt, non-ester, non-amide form. A highly preferred dosage form contains both the adenosylcobalamin and the methylcobalamin (whether in their free form or as a salt or ester or amide of either or each). Preferred dosage amounts of the cobalamin component are a total within a range selected from ranges having a minimum and maximum (with the maximum being greater than the selected minimum) selected from 10 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 62.5 mcg, 75 mcg, 100 mcg, 125 mcg, 250 mcg, 375 mcg, 500 mcg, 625 mcg, 750 mcg, 875 mcg, 1000 mcg, 1200 mcg, 1250 mcg, 1500 mcg, 1600 mcg, 1750 mcg, 1800 mcg, and 2000 mcg, and highly preferred embodiments have a total of the cobalamin content selected from 10 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 62.5 mcg, 75 mcg, 100 mcg, 125 mcg, 250 mcg, 375 mcg, 500 mcg, 625 mcg, 750 mcg, 875 mcg, 1000 mcg, 1200 mcg, 1250 mcg, 1500 mcg, 1600 mcg, 1750 mcg, 1800 mcg, and 2000 mcg, each being calculated based on the non-salt, non-ester, non-amide forms thereof, with dosages intermediary to those stated being equally suitable. Highly preferred dosage forms contain a total of 500 mcg and contain both an adenosylcobalamin and a methyl cobalamin. In a most highly preferred form, the dosage form contains 250 mcg of adenosylcobalamin and 250 mcg of methylcobalamin.

[0054] Vitamin B6 (as pyridoxyl-5-phosphate), when present, is present in an amount to deliver from 0.125 mg of pyridoxine up to 0.375 mg of pyridoxine, most preferably 0.25 mg of pyridoxine per dosage form with intermediary amounts between those specifically stated being suitable as well.

[0055] In addition to the foregoing active agents, the invention formulation can be prepared with a wide range of pharmaceutically acceptable excipients and carriers known in the art, such as binders, disintegrants, dispersants, flow agents, suspending agents, solvents, carrier fluids, flavorings, colorings, buffers, processing aids, etc.

[0056] The compositions of the present invention are generally administered once daily, but if desired, a particular daily dose can be administered in fractional doses multiple times a day.

EXAMPLE 1

Formulation A

[0057] In this Example, the following formulation is prepared. Amounts are given in mg/dosage unit. Where desired, dosage forms having fractional amounts for administration multiple times per day may also be prepared using proportional amounts of the ingredients.

TABLE-US-00001 Ingredient Active Components mg 1-methylfolate glucosamine equivalent to 3.83 mg of 1-methylfolate 1-leucovorin calcium equivalent to 2.4 mg of 1-leucovorin folic acid 2.5 mg adenosylcobalamin 0.25 methylcobalamin 0.25

[0058] The B12 component, whether adenosylcobalamin or methylcobalamin are present in amounts which together are at least 10 mcg per dosage form up to 2000 mcg per dosage form, preferably at least 20 mcg. When a salt or ester or amide of these is used, the amount is an amount which provides the 1-methylfolate glucosamine 1-leucovorin calcium folic acid adenosylcobalamin methylcobalamine

EXAMPLE 2

Formulation B

[0059] In this Example, the following formulation is prepared. Amounts are given in mg/dosage unit. Where desired, dosage forms having fractional amounts for administration multiple times per day may also be prepared using proportional amounts of the ingredients.

TABLE-US-00002 Ingredient Active Components mg 1-methylfolate glucosamine equivalent to 3.83 mg of 1-methylfolate 1-leucovorin calcium equivalent to 2.4 mg of 1-leucovorin folic acid  2.5 mg vitamin B6 (as pyridoxyl 5′ 0.25 mg p-hosphate) adenosylcobalamin 0.25 mg methylcobalamin 0.25 mg

EXAMPLE 3

Use in Depression

[0060] The formulations of Examples 1 and 2 are administered to a patient experiencing depression generally once per day. Where the alternate fractional dosage form is used, the dosage form is administered in the appropriate multiple of times per day.

EXAMPLE 4

Use in Improving Mental Alertness

[0061] The formulations of Examples 1 and 2 are administered to a patient in need of increasing or improving mental alertness generally once per day. Where the alternate fractional dosage form is used, the dosage form is administered in the appropriate multiple of times per day.

[0062] In one example, Examples 1-4 also comprise: a phospholipid from one of the omega-3 fatty acids, such as DHA, EPA or ARA/AA. For example, the phospholipid may be conjugated to a phospholipid moiety selected from phosphatidylserine (PS), phosphatidylethanolamines (PE) or phosphatidylcholines (PC), such as from eggs, with PC being preferred, the amount of phospholipid being in an amount greater than 1 mg and not more than 200 mg of a conjugated phospholipid. The folate composition of claim 1, wherein the types of folate consist of between 0.1 mg and 1 mg of folic acid, between 0.9 mg and 3.9 mg of a folinic acid, and between 1 mg and 14 mg of the 5-methyl-tetrahydrofolic acid. The folic acid may be of a pteroylmonoglutamic acid. The folinic acid may be of a pure 6S isomer, 6S-5-LevoFormylFolic acid. The 5-methyl-tetrahydrofolic may be of a 6S-5-LevoMeFolic acid. Each of these may be found in the USP or merck manual for provitamin B6 (synthetic—folic acid; natural vitamer—folinic; or vitamin B12-coenzyme form of vitamin B9—5-methyl-tetrahydrofolic acid).