WO2009151457A1

WO2009151457A1 - Nutritional preparations

Info

Publication number: WO2009151457A1
Application number: PCT/US2008/066888
Authority: WO
Inventors: John B. Edwards; Lori T. Erlandson; Edward Nicholas Griffin; Alan T. Roberts
Original assignee: Sciele Pharma, Inc.
Priority date: 2008-06-13
Filing date: 2008-06-13
Publication date: 2009-12-17

Abstract

Compositions and methods for improving the nutritional and physiological status of a woman and her child during all stages of pregnancy are provided herein. The compositions are particularly useful for the neurological, visual, and cognitive development of an embryo, fetus, or infant and the nutritional and physiological well-being of the mother, fetus, and infant. The compositions contain one or more folates and one or more essential fatty acids (EFA), such as an omega-3 and/or omega-6 fatty acid. The one or more folates and essential fatty acid may be administered together or in separate dosage units. The compositions may optionally contain other vitamins, minerals, and ingredients.

Description

NUTRITIONAL PREPARATIONS

FIELD OF THE INVENTION

The present invention relates generally to the field of nutrition, and more specifically to nutritional compositions and methods of neurological enhancement.

The invention more specifically relates to nutritional supplements and methods for improving the nutritional and physiological status of women and their fetuses and children before, during, and after pregnancy.

BACKGROUND OF THE INVENTION

Folate is an essential water-soluble B-vitamin that occurs naturally in food. Folic acid is the synthetic form of folate that is commonly found in supplements and added to fortified foods. In 1992, the U.S. Public Health Service recommended that all women of childbearing age consume 400 micrograms (0.4 μg) of folic acid daily. In addition, the U.S. Centers for Disease Control and Prevention (CDC) estimated that if all women of childbearing age took folate, the incidence of birth defects of the brain and spine could be reduced by as much as 70 percent. The recommended daily allowance of folate for males over 14 is 400 micrograms. In 1996, the U.S. Food and Drug Administration (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products. Since cereals and grains are widely consumed in the U.S. diet, these products have become an important contributor of folic acid to the American diet.

Folate helps produce and maintain new cells. This is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to make DNA and RNA. It also helps prevent changes to DNA that may lead to cancer. Both adults and children need folate to make normal red blood cells and prevent anemia, including pregnancy-induced anemia. Folate is also essential for the metabolism of homocysteine and helps maintain normal levels of this amino acid. In a developing embryo or fetus, folate is required for DNA synthesis and repair, helping the baby's brain and spinal cord develop properly. However, folate

US2008 326109 1 must be available in the first 28 days of pregnancy to prevent neural tube defects (NTDs). Further evidence supports additional roles for folate in fetal development later in pregnancy, including the development of the heart, limbs and face. The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.

Folate, commonly supplied as the synthetic form, folic acid, helps reduce the risk of a serious classification of birth defects known as neural tube defects. NTDs often include devastating abnormalities such as spina bifida and anencephaly. About one in every thousand pregnancies is afflicted with a NTD and an estimated 3,000 affected births per year in the United States were reported, prior to the introduction of the folate fortification program. Many additional affected pregnancies result in miscarriage or stillbirth. Spina bifida and anencephaly are severe central nervous system defects that result in serious disability and death. A worldwide estimate of affected pregnancies is approximately 300,000 to 400,000 neural tube defects annually. According to the CDC, approximately 50 to 70 percent of all NTD cases are preventable upon folate supplementation. This would effectively translate to the prevention of 150,000 to 200,000 NTDs worldwide each year.

The majority of infants afflicted with a neural tube defect will survive, but this is a life-altering congenital anomaly often leading to lower body paralysis and sensory loss, loss of bowel and bladder function, and hydrocephalus, which in turn may lead to multiple operations and hospitalizations. The average total lifetime cost for medical care for this disorder has been estimated to exceed a half a million dollars in many instances.

In contrast, anencephaly results when the upper portion of the neural tube fails to fuse. The majority of the brain and brain substance fails to form thus leading to a fatal condition in which a newborn is born with a severely underdeveloped brain and skull.

Folate is an essential nutrient for normal mammalian cell growth as a carrier of single carbon fragments. Folic acid undergoes a series of complicated vitamin and energy-dependent changes in the body, during transport between the intestine and liver. Folate deficiency has been shown to result in uracil misincorporation during DNA replication with subsequent increased double-strand breaks during uracil excision repair. Thus, an increased risk of leukemia-inducing translocations associated with low-folate status is conceivable. Folate coenzymes are required for the metabolism of several important amino acids. The synthesis of methionine from homocysteine requires a folate coenzyme as well as a vitamin Bj₂ dependent enzyme. Thus, folate deficiency can result in decreased synthesis of methionine and a build up of homocysteine. Increased levels of homocysteine may be a risk factor for heart disease, as well as several other chronic diseases.

Folate directed research over the last few years has clearly demonstrated common polymorphisms in folate dependent genes influence the risk of a number of diseases, not merely NTDs. For example, it is well documented that hyperhomocysteinemia is a risk factor for cardiovascular disease.

What is needed are improved compositions to enhance the nutritional and physiological status of women during all stages of pregnancy and the neurological development of a fetus. There is also a need for compositions that improve the quality of breast milk and contribute to enhanced newborn visual, neurological and cognitive development.

It is therefore an object of the present invention to provide improved compositions and methods for enhancing the neurological, visual, and cognitive development of an embryo, fetus, or infant and the nutritional and physiological well- being of the mother, unborn child, or infant before, during, and after pregnancy. It is a more specific object of the present invention to provide improved nutritional preparations containing folate.

It is a further object of the invention to provide improved compositions for the treatment of men and women with a folate deficiency or other conditions associated with folic acid deficiency.

BRIEF SUMMARY OF THE INVENTION

Compositions and methods for improving the nutritional and physiological status of a woman and her child during all stages of pregnancy are provided herein. This includes pre-conceptional women, pregnant women, and post-natal women (both lactating and non-lactating mothers). The compositions are particularly useful for the neurological, visual, and cognitive development of an embryo, fetus, or infant and the nutritional and physiological well-being of the mother, fetus, and infant. The compositions contain one or more folates, such as folic acid, and one or more essential fatty acids (EFA), such as an omega-3 fatty acid and optionally, an omega-6 fatty acid. The addition of the essential fatty acid improves upon the folate nutritional preparations described in the prior art. The one or more folates and the one or more essential fatty acids may be administered together or in separate dosage units. The essential fatty acid is preferably an omega-3 fatty acid, and in one embodiment is docosahexenoic acid (DHA) and/or Eicosapentaenoic acid (EPA), derived from a vegetarian or non-fish source. In another embodiment, the omega-3 fatty acid is derived from algae or fish such as Crypthecodinium cohnii, Schizochytrium, salmon, herring, mackerel, anchovies and sardines. In another embodiment, the omega-3 fatty acid is derived from a botanical source, such as flaxseed (linseed). The compositions may optionally contain other vitamins, minerals, and ingredients, such as, emollient laxatives - defined herein as "optional or other ingredients".

The compositions are beneficial in the development of an embryo's central nervous system (brain and spinal cord). In particular, the compositions are used to aid in the development of the embryo's central nervous system between early embryological stage and late fetal development by administration of the claimed compositions to pregnant or preconceptional women.

The compositions are also directed to post-natal administration to lactating women, thereby supplementing the diet and providing adequate levels of essential vitamins, minerals and other nutrients to breast-fed newborns to aid continued growth and maturity of the brain, nervous system, retina and to assist in cognitive development. The compositions reduce or alleviate fetus- and infant-related folate deficiencies when administered to preconceptional women, pregnant, or post-natal women.

In addition, the compositions provide nutritional and physiological enhancement to women, especially women of childbearing age, preconceptional women or pregnant women by lowering the risk of developing a neural tube defect (NTD) and benefiting the neurological, visual, and cognitive development of an embryo or fetus. The compositions also help to prevent or reduce pregnancy-induced anemia. Furthermore, the compositions can be administered to treat both women and men, having a folate deficiency or other conditions associated with folic acid deficiency.

DETAILED DESCRIPTION OF THE INVENTION I. Compositions

The compositions described herein are compositions containing therapeutically effective amounts of one or more folates and one or more essential fatty acids (EFAs). As used herein, the phrase "one or more folates" is taken to mean that the compositions may contain folic acid or folate. As used herein, the phrase "one or more essential fatty acids" is taken to mean that the compositions may contain 1. one or more omega-3 fatty acids including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA); or 2. one or more omega-6 fatty acids including linoleic acid (LA) and arachidonic acid (AA); or 3. a combination of one or more omega-3 fatty acids and one or more omega-6 fatty acids.

The compositions may optionally contain a therapeutically effective amount of one or more other ingredients such as vitamins, minerals and emollient laxatives. The phrase "an effective amount" or "a therapeutically effective amount" are used interchangeably and include an amount sufficient for 1) improving the nutritional and physiological status of a woman, fetus, or infant and the neurological, visual, and cognitive development of an embryo, fetus, or infant and/or 2) preventing, treating, or ameliorating a neural tube defect or one or more of the symptoms of folate deficiency or a folate metabolic disorder, or other conditions associated with folic acid deficiency and includes an amount which results in the effect that one or more of the symptoms of these disorders are ameliorated or otherwise beneficially altered.

As used herein "composition(s)" and "formulation(s)" are used interchangeably and include preparations such as multivitamins (with or without minerals and other nutrients); breakfast foods such as prepared cereals, toaster pastries and breakfast bars; infant formulas; dietary supplements and complete diet and weight-loss formulas and bars; animal feed (for example pet foods) and animal feed supplements (such as for poultry feed). As used herein, the term "nutritional preparation(s)" is encompassed by the terms "composition(s)" and "formulation(s)" and refers more specifically to multivitamin preparations (with or without minerals and other nutrients) and/or dietary supplements. Both the terms "compositions" and "nutritional preparations" can be taken to mean compositions and preparations where 1) the one or more folates and the one or more essential fatty acids are in the same dosage unit or 2) where the one or more folates and the one or more essential fatty acids are in separate dosage units. In one embodiment the one or more folates, one or more essential fatty acids, and optional other ingredients are contained in the same dosage unit. In another embodiment, the one or more folates and one or more EFAs are in separate dosage units and given together as a single dose. In this embodiment, the other ingredients (vitamins, minerals, and emollient laxative) may be combined with either the one or more folates or the one or more EFAs.

As described above, the compositions are beneficial for improving the nutritional and physiological status of a woman and her child during all stages of pregnancy. This includes pre-conceptional women, pregnant women, and post-natal women (both lactating and non-lactating mothers). As used herein, "nutritional status" refers to the presence or absence of any nutrient deficiency, the extent to which physiological nutrient demands are satisfied such that the deficiency is avoided.

The compositions are also particularly useful for the neurological, visual, and cognitive development of an embryo, fetus, or infant and the nutritional and physiological well-being of the mother, fetus, and infant. "Neurological development" refers to attainment of the highest degree of neurological development possible through natural processes without the use of any unnatural substances or procedures, such as drugs, surgery and the like.

The compositions are also useful for the treatment of men and women with a folate deficiency or a folate metabolic disorder and other conditions associated with folic acid deficiency such as, but not limited to, vascular disease, depression, hyperhomocysteinemia, thrombosis, pregnancy-induced thrombosis, pregnancy- induced anemia, neural tube defects, and homocysteine regulation. "Defective folate metabolic pathway" or "deficient folic acid metabolic pathway" or "folic acid metabolism disorder" refers to a less than normal, lack of, inhibited, or restricted production of folic acid pathway metabolites. The terms also refer to less than normal, deficient or defective levels of folic acid metabolites in a human or other animal. A. Folates

As used herein, the term "folates" includes 1. folic acid, and 2. the anionic form of folic acid, folate. The compositions may contain one or more folates such as a combination of folic acid and folate. A study published in September 2003 by the March of Dimes organization found that less than one-third of American women of childbearing age took a daily multivitamin containing folic acid. As a consequence, by the time many women learn they are pregnant, the crucial period immediately following conception has already passed and any abnormal developments in the neural tube have already occurred. As such, the compositions and methods provided herein are useful for reducing the risks associated with NTDs during pregnancy and aid the neurological development of a fetus prior to, during and after conception.

Therapeutically effective amounts of folate that may be used in the compositions and preparations described herein preferably range from 400 μg to 7 mg. In one embodiment, the amount of folate ranges from 500 μg to 4 mg. In a specific embodiment, the folate is folic acid, present in a range from 600 μg to 1 mg.

2. Folic Acid

The compositions and preparations may comprise folic acid and/or the anionic form of folic acid, folate. Therapeutically effective amounts of folic acid that may be used in the compositions described herein preferably range from about 50 μg to about

6 mg. In another embodiment, the amount of folic acid present in the compositions described herein is about 200 μg and about 2 mg. In a specific embodiment, the amount of folic acid present in the compositions described herein is about 400 μg to about 1 mg. In another embodiment, wherein the compositions are administered to pregnant women as a prenatal supplement and contain folic acid, the amount of folic acid in the composition is at least 200 μg. In a further embodiment, wherein the compositions are administered to pregnant women as a prenatal supplement and contain folic acid, the amount of folic acid in the composition is about 400 μg to approximately 1 mg. B. Essential Fatty Acids

One or more essential fatty acids (EFA), such as an omega-3 fatty acid, or optionally, an omega-6 fatty acid, are included in the folate-containing compositions described above. These compounds are well-known and described in the art, for example, in U.S. Patent Application Publication Nos. 2004/0082523 and 2002/0198177. The omega-3 and omega-6 fatty acids are polyunsaturated fatty acids classified as essential because humans cannot synthesize fatty acids and must obtain them through their diet. The essential omega-3 fatty acids include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA). The human body possesses enzymes that convert ALA to EPA and DHA. Linoleic acid (LA) and arachidonic acid (AA) are examples of omega-6 fatty acids.

In one embodiment, the EFA provided in the compositions is an omega-3 fatty acid or a mixture of omega-3 fatty acids, and preferably contains docosahexaenoic acid (DHA). DHA and vitamin/mineral compositions containing this essential fatty acid are described in detail in U.S. Patent Publication No. 2003/0050341. DHA is one of the main components of brain and heart tissue. It is required for the proper functioning of all neural systems, including the brain, the retina and the central nervous system. In clinical studies, DHA has shown the ability to increase the production of HDL, the so-called good cholesterol. DHA has also shown the ability to inhibit the production of pro-inflammatory prostaglandins. More recently, DHA has been shown to affect neurological function, learning capabilities and behavioral problems such as attention span and the ability to focus. Furthermore, DHA supplementation in infants is reported to facilitate cognitive growth and maturation. Indeed, recent studies report that essential fatty acids enhance fetal cognitive, visual and nervous system maturity. Therefore, it is desirable to administer compositions containing DHA to women of childbearing age to enhance the cognitive development of infants. The brain and nervous tissue undergo a growth spurt from the last trimester of pregnancy to about the first 18 months of life. During this time, an adequate supply of fatty acids are needed to meet the needs of the developing fetus. DHA has been found to be essential for the healthy development of the cerebral cortex of the brain and retina in a baby as well as in an adult. It has been estimated that about half of the quantity of DHA in a fetus' body accumulates in the brain before birth and about half after birth, an indication of the importance of DHA to the fetus during pregnancy and then to the young infant during lactation. A fetus receives docosahexaenoic acid (DHA) from its mother while in the womb. After birth, breast-fed infants receive DHA and other fatty acids from the mother's breast milk and they are also able to make their own DHA. To that end, a mother taking supplements containing DHA during both pregnancy and after childbirth will elevate the DHA levels in her blood thereby supplying the baby. Thus, with regular DHA dosages, the baby will receive adequate levels of DHA for healthy neurological and vision development during prenatal and post-natal periods, and the depleted levels of DHA in the mother are restored.

In addition, the nutritional and health benefits of DHA for the mother are also desirable. For example, supplementation of DHA for a mother has been shown to help in the prevention of depression, including postpartum depression, after the baby is born. Further, the benefits and positive effects of DHA extend well past infancy and into childhood as well. For example, supplementation of DHA in the nutritional regimen of a child has been found to be desirable in the prevention of attention deficit/hyperactivity disorder in children.

In one embodiment, the DHA may be relatively free (<10%, and preferably <5%) of omega-6 fatty acids, such as linoleic acid or arachidonic acid. In another embodiment, the compositions contain linoleic acid in concentrations less than or equal to 5% by weight of DHA raw materials. In another embodiment, the DHA component of the compositions and preparations contain at least about 20% DHA relative to omega-6 fatty acids. Furthermore, administering the compositions comprising DHA to a pregnant woman allows for the stable neurological development of an embryo or fetus.

In one embodiment, the compositions may contain EFA that are substantially free (<10%, and preferably <5%) of omega-6 fatty acids, such as linoleic acid or arachidonic acid.

DHA and EPA are available as fish oil extracts. However, compositions containing fish-derived DHA, for example, may have a potent, offensive taste or odor. Additionally, substances derived from fish are believed to contain contaminants such as pollutants or ocean-borne contaminants, including dioxin and mercury, which can be detrimental to a developing embryo. Therefore, it is desirable to use DHA derived from a natural source, in one embodiment the DHA is derived from a vegetarian or non-fish source. In another embodiment, the compositions are formulated to comprise DHA derived from a vegetarian source such as, but not limited to, algae. In one embodiment, the compositions include DHA derived from the alga species Crypthecodinium cohnii. Methods for the production of DHA from algae are described in the following patents, U.S. Patents 5,130,242, 5,340,742, 5,340,594, 6,451,567, 6,509,178, and 6,607,900.

The algae-derived DHA compositions satisfy the unmet needs of the prior art because the instant compositions are free from fish oil, fish matter, or other fish products. Both the U.S. Food and Drug Administration and the Environmental Protection Agency advise women who become pregnant, or are pregnant or nursing, to limit their intake of certain fish due to findings that certain fish contain significant levels of ocean-borne contaminants. The compositions of the instant invention provide additional benefit over the prior art because the compositions may contain algae-derived DHA that is not derived from fish, thereby eliminating a fishy smell or taste that is often reported and associated with fish and fish oil products. This is a significant development for pregnant women who frequently suffer from morning- sickness or nausea, that can be induced by potent or over-powering odors or tastes.

As stated above, the one or more EFAs can be contained within the same dosage unit as the one or more folates or may be in a separate dosage unit. In one embodiment, the essential fatty acid is provided as a separate capsule that is substantially free of other vitamins or minerals. The one or more EFAs may be presented in a hard capsule, such as, but not limited to, a hard gelatin capsule, or a soft gelatin (softgel) capsule. In one embodiment, the one or more EFAs are presented in an encapsulated semi-solid or liquid form. In another embodiment, the EFA component is presented in a semi-solid or liquid form packaged in a soft gelatin (softgel) capsule. In one embodiment, the soft gelatin capsule is prepared from vegetable or plant based materials. In a further embodiment, the soft gelatin capsules are made from cellulosic raw materials. In another embodiment the soft gelatin capsules are preservative-free, easy to swallow, effectively mask taste and odor, and allow product visibility. Furthermore, in a specific embodiment, the EFA soft gelatin capsules prepared from plant or vegetable origins meet the strict dietary needs of individuals that choose vegetarian, as well as Kosher, lifestyles. Therapeutically effective amounts of essential fatty acids that may be used in the compositions and preparations preferably range from about 100 mg to about 1 g. In one embodiment, the amount of the EFA present in the compositions and preparations ranges from about 200 mg to about 800 mg. In another embodiment, the essential fatty acid is DHA present in the compositions and preparations in a range of from about 250 mg to about 500 mg. In a further embodiment, wherein the compositions comprise a DHA softgel capsule, the DHA softgel capsule may optionally contain DHA that is essentially free of other vitamins, minerals and Omega-3 fatty acids. In another embodiment, the DHA softgel capsule may optionally comprise a DHA softgel capsule that is essentially free of omega-6 fatty acids. In a further embodiment, the DHA softgel capsule may optionally comprise a DHA softgel capsule that is essentially free of eicosapentaenoic acid.

C. Other Vitamins, Minerals, and Ingredients

1. Iron The compositions may optionally include an iron compound or derivatives thereof. In one embodiment, an effective amount of iron in the compositions ranges from about 10 mg to about 200 mg of iron compound or derivative. In one embodiment, the iron compound is elemental iron. In another embodiment, the iron compound is carbonyl iron in a range of from about 80 mg to about 130 mg, and preferably 90 mg. In an alternative embodiment, the iron compound is an iron salt or combinations thereof, including, but not limited to, ferrous sulfate, ferrous fumarate, ferrous succinate, ferrous gluconate, ferrous lactate, ferrous glutamate or ferrous glycinate in a range of from about 10 mg to about 80 mg.

2. Copper The compositions may optionally include a copper compound or derivatives thereof. Preferably, the amount of copper in the compositions ranges from about 0.1 mg to about 10 mg of copper compound or derivative. In one embodiment, the amount of copper in the compositions ranges from about 1 mg to about 5 mg. In a specific embodiment, the amount of copper in the compositions ranges from about 1.0 mg to about 2.5 mg. In another embodiment, the copper compound is cupric oxide or copper sulfate.

3. Zinc The compositions may optionally include a zinc compound or derivatives thereof. Preferably, the amount of zinc in the compositions ranges from about 5 mg to about 100 mg of zinc compound or derivative. In one embodiment, the amount of zinc in the compositions ranges from about 6 mg to about 30 mg. In a specific embodiment, the amount of zinc in the compositions ranges from about 10 mg to about 20 mg. In another embodiment, the zinc compound is zinc oxide.

4. Magnesium

The compositions may optionally include a magnesium compound or derivatives thereof. Preferably, the amount of magnesium in the compositions ranges from about 5 mg to about 400 mg of magnesium compound or derivative. In one embodiment, the amount of magnesium in the compositions ranges from about 10 mg to about 200 mg. In a specific embodiment, the amount of magnesium in the compositions ranges from about 20 mg to about 100 mg. In one embodiment, the magnesium compound is magnesium oxide. Biologically-acceptable magnesium compounds which may be incorporated into the present inventive subject matter include, but are not limited to, magnesium stearate, magnesium carbonate, magnesium oxide, magnesium hydroxide and magnesium sulfate.

5. Calcium

The compositions may optionally include a calcium compound or derivatives thereof. Preferably, the amount of calcium in the compositions ranges from about 20 mg to about 2500 mg of calcium compound or derivative. In one embodiment, the amount of calcium in the compositions ranges from about 150 mg to about 2000 mg.

In a specific embodiment, the amount of calcium in the compositions ranges from about 175 mg to about 500 mg. Biologically-acceptable calcium compounds include, but are not limited to, any of the well known calcium supplements, such as calcium carbonate, calcium pantothenate, calcium sulfate, calcium oxide, calcium hydroxide, calcium apatite, calcium citrate-malate, bone meal, oyster shell, calcium gluconate, calcium lactate, calcium phosphate, calcium levulinate, and the like.

6. Vitamin Bi The formulations of the compositions described herein may optionally contain vitamin Bi (thiamine mononitrate) or derivatives thereof. Derivatives of vitamin B) include compounds formed from vitamin Bi that are structurally distinct from vitamin Bi, but that retain the active function of vitamin Bi. The vitamin Bi may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin Bi in the compositions preferably ranges from about 0.5 mg to about 50 mg. In one embodiment, the amount of vitamin Bi in the compositions ranges from about 1 mg to about 4 mg. In a specific embodiment, the amount of vitamin Bi in the compositions ranges from about 1.0 mg to about 3.0 mg.

7. Vitamin B₂

The formulations may optionally include vitamin B₂ (riboflavin) or derivatives thereof. Derivatives of vitamin B₂ include compounds formed from vitamin B₂ that are structurally distinct from vitamin B₂, but that retain the active function of vitamin

B₂. The vitamin B₂ may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin B₂ in the compositions preferably ranges from about 0.5 mg to about 50 mg. In one embodiment, the amount of vitamin B₂ in the compositions ranges from about 1 mg to about 4.5 mg. In a specific embodiment, the amount of vitamin B₂ in the compositions ranges from about 1.5 mg to about 3.8 mg.

8. Vitamin B₆

The formulations may optionally contain vitamin B₆ (pyridoxine HCl) or derivatives thereof. Derivatives of vitamin B₆ include compounds formed from vitamin B₆ that are structurally distinct from vitamin B₆, but that retain the active function of vitamin B₆. The vitamin B₆ may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin B₆ in the compositions preferably ranges from about 0.1 mg to about 200 mg. In one embodiment, the amount of vitamin B₆ in the compositions ranges from about

1 mg to about 90 mg. In a specific embodiment, the amount of vitamin B₆ in the compositions ranges from about 2 mg to about 50 mg.

9. Vitamin Bi₂

The compositions may optionally include a vitamin Bi₂ or one of the three active forms: cyanocobalamin, hydroxocobalamin, or nitrocobalamin, or derivatives thereof. The derivatives of vitamin Bi₂ include compounds formed from vitamin Bi₂ that are structurally distinct from vitamin Bj₂, but that retain the active function of vitamin Bi₂. Non-limiting examples of such derivatives include methylcobalamin, deoxyadenosylobalamin, combinations thereof and the like. Preferably, the amount of vitamin Bj₂ in the instant compositions of the invention ranges from about 1 μg to about 250 μg. In one embodiment, the amount of vitamin B ₁₂ in the compositions ranges from about 2 μg to about 30 μg. In a specific embodiment, the amount of vitamin Bj₂ in the compositions ranges from about 5 μg to about 20 μg.

10. Vitamin D₃

The formulations may optionally contain vitamin D₃ (cholecalciferol) or derivatives thereof. Derivatives of vitamin D₃ include compounds formed from vitamin D₃ that are structurally distinct from vitamin D₃, but that retain the active function of vitamin D₃. The vitamin D₃ may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin D₃ in the compositions preferably ranges from about 1 IU to about 2000 IU. In one embodiment, the amount of vitamin D₃ in the compositions ranges from about 100 IU to about 1500 IU. In a specific embodiment, the amount of vitamin D₃ in the compositions ranges from about 200 IU to about 1000 IU.

11. Vitamin E

The formulations may optionally include vitamin E (dl-alpha tocopheryl acetate) or derivatives thereof. Derivatives of vitamin E include compounds formed from vitamin E that are structurally distinct from vitamin E, but that retain the active function of vitamin E. The vitamin E may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin E in the compositions preferably ranges from about 1 IU to about 1000 IU. In one embodiment, the amount of vitamin E in the compositions ranges from about 5 IU to about 500 IU. In a specific embodiment, the amount of vitamin E in the compositions ranges from about 8 IU to about 200 IU.

12. Vitamin C

The formulations described herein may optionally include vitamin C (ascorbic acid) or derivatives thereof. Derivatives of vitamin C include compounds formed from vitamin C that are structurally distinct from vitamin C, but that retain the active function of vitamin C. The vitamin C may be present in a single form or in various different forms in combination within the present compositions. The amount of vitamin C in the compositions preferably ranges from about 10 mg to about 2000 mg. In one embodiment, the amount of vitamin C in the compositions ranges from about 40 mg to about 1000 mg. In another embodiment, the amount of vitamin C in the compositions ranges from about 50 mg to about 500 mg. 13. Biotin

The formulations may optionally contain biotin or derivatives thereof. Derivatives of biotin include compounds formed from biotin that are structurally distinct from biotin, but that retain the active function of biotin. The biotin may be present in a single form or in various different forms in combination within the present compositions. The amount of biotin in the composition ranges from about 10 μg to about 50 μg. In one embodiment, the amount of biotin in the compositions ranges from about 20 μg to about 40 μg. In another embodiment, the amount of biotin in the compositions ranges from about 25 μg to about 35 μg. 14. Pantothenic Acid The formulations may optionally include pantothenic acid (calcium pantothenate) or derivatives thereof. Derivatives of pantothenic acid include compounds formed from pantothenic acid that are structurally distinct from pantothenic acid, but that retain the active function of pantothenic acid. The pantothenic acid may be present in a single form or in various different forms in combination within the present compositions. The amount of pantothenic acid in the compositions preferably ranges from about 1 mg to about 50 mg. In one embodiment, the amount of pantothenic acid in the compositions ranges from about 3 mg to about 12 mg. In another embodiment, the amount of pantothenic acid in the compositions ranges from about 5 mg to about 10 mg. 15. Niacinamide

The formulations may optionally include niacinamide or derivatives thereof. Derivatives of niacinamide include compounds formed from niacinamide that are structurally distinct from niacinamide, but that retain the active function of niacinamide. The niacinamide may be present in a single form or in various different forms in combination within the present compositions. The amount of niacinamide in the compositions preferably ranges from about 1 mg to about 100 mg. In one embodiment, the amount of niacinamide in the compositions ranges from about 10 mg to about 30 mg. In another embodiment, the amount of niacinamide in the compositions ranges from about 15 mg to about 25 mg.

16. Vitamin A

The formulations may optionally include vitamin A from any commonly known source, for example, retinol or beta-carotene. Preferably, the source of vitamin

A is beta-carotene. In one embodiment, vitamin A is provided in a total daily dose of between 0-10,000 LU. In another embodiment, vitamin A is provided in a total daily dose of between 2,000 and 5,000 IU.

17. Manganese The compositions may optionally include a manganese compound or derivative thereof. Preferably, the amount of manganese in the compositions ranges from about 0.5 mg to about 50 mg of manganese compound or derivative. In one embodiment, the amount of manganese in the compositions ranges from about 1 mg to about 20 mg. In another embodiment, the amount of manganese in the compositions ranges from about 1 mg to about 10 mg. In one embodiment, the manganese compound is manganese sulfate. Biologically-acceptable manganese compounds which may be incorporated into the present inventive subject matter include, but are not limited to, manganese chloride, manganese carbonate, manganese gluconate, magnesium citrate and manganese sulfate. 18. Selenium

The compositions may optionally include a selenium compound or derivative thereof. Preferably, the amount of selenium in the compositions ranges from about 5 μg to about 100 μg of selenium compound or derivative. In one embodiment, the amount of selenium in the compositions ranges from about 10 μg to about 50 μg. In another embodiment, the amount of selenium in the compositions ranges from about 20 μg to about 40 μg. In one embodiment, the selenium compound is a sodium selenite. Biologically-acceptable selenium compounds which may be incorporated into the present inventive subject matter include, but are not limited to, sodium hydrogen selenite and sodium selenite. 19. Iodine

The compositions may optionally include a iodine compound or derivatives thereof. Preferably, the amount of iodine in the compositions ranges from about 50 μg mg to about 300 μg of iodine compound or derivative. In one embodiment, the amount of iodine in the compositions ranges from about 100 μg to about 200 μg. In another embodiment, the amount of iodine in the compositions ranges from about 150 μg to about 200 μg. In one embodiment, the iodine compound is potassium iodine. Biologically-acceptable iodine compounds which may be incorporated into the present inventive subject matter include, but are not limited to, sodium iodide and potassium iodide.

20. Molybdenum

The compositions may optionally include a molybdenum compound or derivatives thereof. Preferably, the amount of molybdenum in the compositions ranges from about 10 μg mg to about 300 μg of molybdenum compound or derivative.

In one embodiment, the amount of molybdenum in the compositions ranges from about 20 μg to about 200 μg. In another embodiment, the amount of molybdenum in the compositions ranges from about 25 μg to about 50 μg. In one embodiment, the molybdenum compound is sodium molybdate. Biologically-acceptable molybdenum compounds which may be incorporated into the present inventive subject matter include, but are not limited to, elemental molybdenum, ammonium molybdate

(molybdenum (VI)) and sodium molybdate (molybdenum (VI)).

21. Emollient Laxatives In one embodiment, the compositions optionally include an emollient laxative.

The term "emollient laxative" is used herein to define a stool softener. In one embodiment, the emollient laxative is sodium docusate, glycerin, mineral oil or a poloxamer. In another embodiment, the emollient laxative is a pharmaceutically acceptable salt of docusate, such as, but not limited to, calcium. In another embodiment, the amount of emollient laxative provided in the instant compositions is between approximately 50 mg and approximately 1 g. In another embodiment, wherein the compositions are administered to pregnant women as a prenatal supplement the amount of emollient laxative in the composition is about 50 to about 200 mg. In a further embodiment, wherein the compositions are administered to pregnant women as a prenatal supplement, the amount of emollient laxative in the composition is about 50 mg. D. Salts and Derivatives

Although described above with reference specific to compounds, one can also utilize enantiomers, stereoisomers, derivatives and salts of the active compounds. Methods for synthesis of these compounds are known to those skilled in the art. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethane disulfonic, oxalic and isethionic acids. The pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, PA, 1985, p. 1418).

E. Formulations In one embodiment, the one or more folates, one or more essential fatty acids and optional ingredients such as vitamins, minerals, and emollient laxatives can be formulated in the same dosage unit. As used herein, "dosage unit" means any pharmaceutically acceptable form for administering a drug to a patient, including, but not limited to, capsules, soft-gel capsules, tablets, buccal forms, troches, lozenges, oral liquids, suspensions or solutions. In another embodiment, the one or more folates and optional ingredients are formulated into one dosage unit and the one or more EFAs are formulated in a separate dosage unit. In one embodiment, the one or more folates and optional ingredients are formulated into a tablet, and the one or more essential fatty acids are formulated as a semi-solid or liquid in a separate softgel capsule. Softgels may be prepared, for example, without limitation, by dispersing the formulation in an appropriate vehicle to form a high viscosity mixture. This mixture is then encapsulated with a gelatin or vegetable based material using technology and machinery known to those in the softgel industry. The compositions comprising at least one tablet containing one or more folates and at least one softgel EFA capsule are presented together in one packing material. In another embodiment, the at least one softgel EFA capsule and the at least one tablet, are presented together within one blister-pack.

Film coated tablets, for example, without limitation, may be prepared by coating tablets using techniques such as, but not limited to, rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet. This procedure is often done to improve the aesthetic appearance of tablets, but may also be done to improve the ease of swallowing of tablets, or to mask an odor or taste. The compositions may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. The compositions may be provided in a blister-pack or other such pharmaceutical package, without limitation. Further, the compositions may further include or be accompanied by indicia allowing a person to identify the compositions as products for women planning to conceive or who are pregnant. The indicia may further additionally include an indication of the above specified time periods for using said compositions.

Preferably, the compounds are orally administered. For oral administration, the compounds, particularly their acid addition salts, are formed into tablets, granules, powders or capsules containing suitable amounts of granules or powders by a conventional method together with usual drug additives. Oral formulations containing the active compounds may be in any conventionally used oral form, including tablets, capsules, softgel capsules, buccal forms, troches, lozenges, oral liquids, suspensions or solutions. Oral formulations may utilize standard delay or time release formulations to alter the absorption of the active compound(s).

Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975), and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980). The active compounds (or pharmaceutically acceptable salts thereof) may be administered in the form of a pharmaceutical composition wherein the active compound(s) is in admixture or mixture with one or more pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT^® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. Optional pharmaceutically acceptable excipients present in the drug- containing tablets, capsules, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4- oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer^® 401 , stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-.beta.- alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

Blending or copolymerization sufficient to provide a certain amount of hydrophilic character can be useful to improve wettability of the materials. For example, about 5% to about 20% of monomers may be hydrophilic monomers. Hydrophilic polymers such as hydroxylpropylcellulose (HPC), hydroxpropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) are commonly used for this purpose. Also suitable are hydrophobic polymers such as polyesters and polyimides. It is known to those skilled in the art that these polymers may be blended with polyanhydrides to achieve compositions with different drug release profiles and mechanical strengths. Preferably, the polymers are bioerodable, with preferred molecular weights ranging from 1000 to 15,000 kDa, and most preferably 2000 to 5000 Da. The compounds may be complexed with other agents as part of their being pharmaceutically formulated. The pharmaceutical compositions may take the form of, for example, tablets, capsules or softgel capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose); fillers (e.g., corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, or alginic acid); lubricants (e.g. magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica); and disintegrators (e.g. micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid). If water-soluble, such formulated complex then may be formulated in an appropriate buffer, for example, phosphate buffered saline or other physiologically compatible solutions. Alternatively, if the resulting complex has poor solubility in aqueous solvents, then it may be formulated with a non-ionic surfactant such as TWEEN™, or polyethylene glycol. Thus, the compounds and their physiologically acceptable solvates may be formulated for administration.

Delayed release and extended release compositions can be prepared according to methods readily known in the art. The delayed release/extended release pharmaceutical compositions can be obtained by complexing drug with a pharmaceutically acceptable ion-exchange resin and coating such complexes. The formulations are coated with a substance that will act as a barrier to control the diffusion of the drug from its core complex into the gastrointestinal fluids. Optionally, the formulation is coated with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the basic environment of lower GI tract in order to obtain a final dosage form that releases less than 10% of the drug dose within the stomach

Examples of rate controlling polymers that may be used in the dosage form are hydroxypropylmethylcellulose (HPMC) with viscosities of either 5, 50, 100 or 4000 cps or blends of the different viscosities, ethylcellulose, methylmethacrylates, such as Eudragit RSlOO, Eudragit RLlOO, Eudragit NE 30D (supplied by Rohm America). Gastrosoluble polymers, such as Eudragit ElOO or enteric polymers such as Eudragit L100-55D, LlOO and SlOO may be blended with rate controlling polymers to achieve pH dependent release kinetics. Other hydrophilic polymers such as alginate, polyethylene oxide, carboxymethylcellulose, and hydroxyethylcellulose may be used as rate controlling polymers. II. Methods of Use

A. Administration Protocol The compositions of the present invention may involve the administration of the compositions at one or more times during a 24 hour period. For example, the compositions may be administered as a single dose of one or more tablets, capsules or softgel capsules during a 24 hour period of time. In another embodiment, the compositions are administered in a once daily dose. The compositions are preferably administered prior to, during or after pregnancy. In one embodiment, the compositions and preparations are administered during a period of time commencing prior to conception and continuing through to completion of breast-feeding or continuing on as a nutritional supplement for the mother. The compositions and preparations may be given to both lactating and non- lactating mothers.

The compositions may be modified in dosage as required by one skilled in the art. In one embodiment, the dosage can be modified by one skilled in the art to treat or prevent a disease or disorder, or lessen the risks associated with a nutritional disorder. In one embodiment, the dosage can be modified to treat a folate deficiency. In another embodiment, the dosage can be modified to provide preventative levels of folates to a woman who is planning to conceive or who is pregnant. In an alternative embodiment, the dosage can be modified to provide preventative levels of folates to a woman whose previous fetus developed a NTD in utero. In another embodiment, the dosage can be modified by one skilled in the art to provide adequate or normal levels of folates to a woman who is pregnant with multiple fetuses and thus requires increased levels of folate. The methods are generally applicable to males and females unless expressively stated to the contrary. The methods are also applicable to healthy and ill individuals, and are particularly suitable for individuals with a folic acid deficiency. Furthermore, the methods are applicable to preconceptional or pregnant women to reduce the risk of developing a NTD during pregnancy. In another embodiment, the methods are applicable to preconceptional, pregnant, or post-natal women to enhance the neurological and cognitive development of an embryo, fetus, or infant. In one embodiment, the methods of the invention are applicable as a prophylactic treatment of a disease or disorder associated with a folic acid deficiency in humans or other animals.

EXAMPLES

Example 1

A nutritional preparation including folic acid, omega-3 fatty acids (EPA and

DHA) and optionally, a stool softener. A composition comprising the following constituents suitable for oral application is formed by: admixing folic acid, omega-3 fatty acids and optionally, docusate sodium to form a mixture; and processing the mixture to form tablets, capsules or softgel capsules; wherein the composition includes:

400 μg folic acid; 240 mg omega-3 fatty acids; provided as 87 mg DHA and 131 mg EPA as ethyl esters; and 50 mg docusate sodium (optional)

Example 2 A nutritional preparation including folic acid, DHA and optionally, a stool softener. A composition comprising the following constituents suitable for oral application is formed by: admixing folic acid, DHA and optionally, a stool softener to form a mixture; and processing the mixture to form tablets, capsules, or softgel capsules; wherein the composition includes.

400 μg folic acid;

87 mg DHA; and

50 mg docusate sodium (optional)

Example 3

A nutritional preparation including folic acid, DHA and optionally, calcium, and a stool softener. A composition comprising the following constituents suitable for oral application is formed by: admixing folic acid, DHA, and optionally calcium, and a stool softener to form a mixture; and processing the mixture to form tablets, capsules or softgel capsules; wherein the composition includes:

400 μg folic acid; 100 mg calcium (optional); 87 mg DHA; and 50 mg docusate sodium (optional).

Example 4

A nutritional preparation including folic acid, DHA, and optionally iron, and a stool softener. A composition comprising the following constituents suitable for oral administration is formed by: admixing folic acid, DHA, and optionally iron, and a stool softener to form a mixture; and processing the mixture to form tablets or capsules; wherein the compositions includes:

400 μg folic acid;

10 mg iron (optional);

87 mg DHA; and

50 mg docusate sodium (optional).

Example 5

A nutritional preparation including folic acid, DHA, and optionally vitamin

B i₂, and a stool softener. A composition comprising the following constituents suitable for oral application is formed by: admixing folic acid, DHA, and optionally vitamin Bi₂, and a stool softener to form a mixture; and processing the mixture to form tablets or capsules; wherein the composition includes:

400 μg folic acid 5 μg vitamin Bi₂ (optional): 87 mg DHA; and 50 mg docusate sodium (optional).

Example 6

A nutritional preparation including folic acid, omega-3 fatty acids and optionally vitamin B_]2, vitamin Be, vitamin B₂, vitamin Bi₁ vitamin D3, vitamin C, vitamin E, and a stool softener. A composition comprising the following constituents suitable for oral application is formed by: admixing folic acid, omega-3 fatty acids, and optionally vitamin Bi₂, vitamin B₆, vitamin B₂, vitamin Bi₁ vitamin D₃, vitamin C, vitamin E, and a stool softener to form a mixture; and processing the mixture to form tablets or capsules; wherein the composition includes:

480 μg folic acid ; 240 mg omega-3 fatty acids; provided as 87 mg DHA and 131 mg EPA as ethyl esters;

6 μg vitamin D₃ (optional); 10 IU vitamin E (optional); 84 mg vitamin C (optional); 1.5 mg vitamin B] (optional); 1.75 mg vitamin B₂ (optional); 2 mg vitamin B₆ (optional); 5.25 μg vitamin Bi₂ (optional); and 50 mg docusate sodium (optional).

In all of Examples 1-6 above, DHA or EFA may be provided separately from the other ingredients for example, in a softgel capsule, as described in detail in the preceding sections.

Example 7.

The following nutritional preparation may be used for administration to preconceptional and pregnant women to reduce the risk of neural tube defects during pregnancy and to enhance the neurological and cognitive development of an embryo or fetus. It may also be used to improve the nutritional status of the woman throughout pregnancy and in the postnatal period for both lactating and non-lactating mothers. In addition, the preparation may be used for administration to breast feeding mothers to provide newborns with essential vitamins and nutrients to aid in continued growth and maturity of the brain, nervous system, and retina and to assist in cognitive development. Furthermore, it may be used to prepare preconceptional supplement products for administration to preconceptional women to improve the nutritional status of the woman prior to conception. A preparation containing: Elemental Iron 10-200 mg;

Biotin 10-50 meg;

Pantothenic acid 5-50 mg;

Calcium 20-2500 mg;

Copper 0.1-10 mg; Zinc 5-100 mg;

Folate 400-7,000 meg;

Vitamin D₃ (cholecalciferol) 1 -2,000 IU;

Vitamin E (dl-alpha tocopheryl) 1-1000 IU; Vitamin C (ascorbic acid) 10-2000 mg;

Vitamin Bi (thiamine) 0.5-50 mg;

Vitamin B₂ (riboflavin) 0.5-50 mg;

Vitamin Be (pyridoxine) 0.1-200 mg ;

Vitamin Bi₂ (cyanocobalamin) 1-250 meg ; Niacinamide 1-100 mg;

Magnesium 5-400 mg;

Docusate Sodium, USP 50-1000 mg.

DHA 100-1 ,000 mg.

Betacarotene (optional) 0- 10,000 IU

The DHA may be provided in the same dosage unit or a separate dosage unit as the other vitamins, minerals, and ingredients. In another embodiment, the nutritional preparation does not contain betacarotene.

Example 8

A similar nutritional preparation as that described in Example 7 with the preferred amounts of the vitamins, minerals, and ingredients is as follows.

A soft-gel capsule containing:

Iron (ferrous fumarate) 14 mg;

Biotin 30-50 meg;

Pantothenic acid (calcium pantothenate, USP) 10.5 mg; Calcium (calcium carbonate, USP) 100 mg;

Copper (copper sulfate) 1 mg;

Zinc (zinc oxide, USP) 9.5-12 mg;

Folic acid, USP 400-480 meg;

Vitamin D₃ (cholecalciferol) 6 μg; Vitamin E (dl-alpha tocopheryl acetate) 9.5-12.5 mg;

Vitamin C (ascorbic acid, USP) 70-85 mg;

Vitamin Bi (thiamine mononitrate) 1.2-1 .5 mg;

Vitamin B₂ (riboflavin, USP) 1.6-1.8 mg;

Vitamin Be (free base) 2-2.7 mg; Vitamin Bi₂ (cyanocobalamin) 3-5.25 meg;

Niacinamide, USP 18-20 mg;

Magnesium (magnesium oxide. USP) 50 mg;

Selenium (sodium selenite) 25 μg;

Manganese (manganese sulfate) 1 mg; Iodine (potassium iodide) 150 μg;

Molybdenum (sodium molybdate) 25 μg; and

Fish oil (30%EPA/20% DHA (as EE)) 240-450 mg. Compositions incorporating the above formulation are prepared using conventional methods and materials known in the pharmaceutical art. The resulting folate supplements are recovered and stored for future use.

It is understood that the disclosed methods are not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:

L A nutritional preparation comprising one or more folates and one or more essential fatty acids.

2. The nutritional preparation of claim 1, wherein the one or more essential fatty acids is an omega-3 fatty acid.

3. The nutritional preparation of claim 2, wherein the one or more essential fatty acids is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and mixtures thereof.

4. The nutritional preparation of claim 1, wherein the one or more essential fatty acids is docosahexaenoic acid that is substantially free of other omega- 3 fatty acids.

5. The nutritional preparation of claim 4, wherein the docosahexaenoic acid is derived from a vegetarian source.

6. The nutritional preparation of claim 5, wherein the vegetarian source is algae.

7. The nutritional preparation of claim 1, wherein the one or more folates is folic acid.

8. The nutritional preparation of claim 1 wherein the preparation further comprises one or more ingredients selected from the group consisting of emollient laxatives; vitamins; and minerals.

9. The nutritional preparation of claim 1, wherein the one or more folates and the one or more essential fatty acids are in the same dosage unit.

10. The nutritional preparation of claim 1, wherein the one or more folates and the one or more essential fatty acids are in separate dosage units.

1 1. The nutritional preparation of claim 10, wherein the dosage unit containing the one or more folates further comprises one or more ingredients selected from the group consisting of emollient laxatives; vitamins; and minerals.

12. The nutritional preparation of claim 10, wherein the dosage unit containing the one or more folates and the dosage unit containing the one or more essential fatty acids are packaged together.

13. The nutritional preparation of claim 12, wherein the dosage units are packaged together in a blister pack.

14. A nutritional preparation comprising folic acid and docosahexaenoic acid that is substantially free of other omega-3 fatty acids.

15. The nutritional preparation of claim 14, wherein the nutritional preparation is substantially free of omega-6 fatty acids.

16. The nutritional preparation of claim 14, wherein the docosahexaenoic acid is derived from a vegetarian source.

17. The nutritional preparation of claim 14, wherein the preparation further comprises one or more ingredients selected from the group consisting of emollient laxatives; vitamins; and minerals.

18. The nutritional preparation of claim 14, wherein the folic acid and the one or more essential fatty acids are in the same dosage unit.

19. The nutritional preparation of claim 14, wherein the folic acid and the one or more essential fatty acids are in separate dosage units.

20. A method of improving the nutritional status of a woman throughout pregnancy and in the postnatal period comprising administering a therapeutically effective amount of one or more folates and one or more essential fatty acids to the woman prior to, during, or following pregnancy.

21. The method of Claim 20, wherein the one or more essential fatty acids is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and mixtures thereof.

22. The method of Claim 20, wherein the one or more essential fatty acids is docosahexaenoic acid (DHA) that is substantially free of other omega-3 fatty acids.

23. The method of Claim 20, wherein the one or more essential fatty acids is docosahexaenoic acid (DHA) that is substantially free of omega-6 fatty acids.

24. A method for promoting the development of the central nervous system of an embryo or fetus between early embryological stage and late fetal development comprising administering a therapeutically effective amount of one or more folates and one or more essential fatty acids to a preconceptional or pregnant woman carrying the embryo or fetus.

25. The method of claim 24, wherein the one or more folates and one or more essential fatty acids are administered in the same dosage unit.

26. The method of claim 24, wherein, the one or more folates and one or more essential fatty acids are administered in separate dosage units.

27. The method of claim 24, wherein the separate dosage units are administered at the same time.

28. The method of claim 24, wherein the one or more essential fatty acids is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and mixtures thereof.

29. The method of claim 24, wherein the one or more essential fatty acids is docosahexaenoic acid (DHA) that is substantially free of other omega-3 fatty acids.

30. A method for promoting the development of the central nervous system of an infant nursing from a lactating female comprising administering to the lactating female a therapeutically effective amount of one or more folates and one or more essential fatty acids.

31. The method of claim 30, wherein the one or more essential fatty acids is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and mixtures thereof.

32. The method of claim 30, wherein the one or more essential fatty acids is docosahexaenoic acid (DHA) that is substantially free of other omega-3 fatty acids.

33. A method for reducing the risk of a fetus developing a neural tube defect in utero comprising administrating to a woman prior to, or during pregnancy, a therapeutically effective amount of one or more folates and one or more essential fatty acids.

34. The method of claim 33, wherein the one or more essential fatty acids is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and mixtures thereof.

35. The method of claim 33, wherein the one or more essential fatty acids is docosahexaenoic acid (DHA) that is substantially free of other omega-3 fatty acids.