US 2005O143340A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0143340 A1 Collins (43) Pub. Date: Jun. 30, 2005

(54) ADENOSYL-COBALAMIN FORTIFIED Related U.S. Application Data COMPOSITIONS (63) Continuation of application No. 10/176,138, filed on (76) Inventor: Douglas A. Collins, Rochester, MN Jun. 20, 2002, now abandoned. (US)US (60) Provisional application No. 60/299,797, filed on Jun. Correspondence Address: 20, 2001. KING & SPALDING LLP Publication Classification 191 PEACHTREE STREET, N.E.

45TH FLOOR (51) Int. CI.7. ... A23L 1/30; A61K 31/714 ATLANTA, GA 30303-1763 (US) (52) U.S. Cl...... 514/52; 426/72 (57) ABSTRACT (21) Appl. No.: 11/069,796 The invention provides food, drink, Supplement or other compositions containing a fortifying amount of adenosyl (22) Filed: Feb. 28, 2005 cobalamin. Patent Application Publication Jun. 30, 2005 US 2005/0143340 A1

HN N

N N N1 OH O b OH

NH go C HN O a. H CH O

HN N CH3. H d A || B Q A N NS O o CH \ ^ NH HC / -- N / H 2 2 HN N. N. N CH D | C HH3C N H CH

H

O NH (P f O NH g= 6

Sr.,O oO N

- HON

O HO

FIGURE 1 US 2005/0143340 A1 Jun. 30, 2005

ADENOSYL-COBALAMIN FORTIFIED cobalt (Co) or side chains is called corrin and the octade COMPOSITIONS hydrocorrin is called corrole. The corrin ring has attached seven amidoalkyl (H2NC(O)Alk) substituents, at the 2, 3, 7, 0001. This application claims priority to U.S. provisional 8, 13, 18 and 23 positions, which can be designated a-g application 60/299,797 filed on Jun. 20, 2001. respectively. See D. L. Anton et al., J. Amer: Chem. Soc., 102, 2215 (1980). The 2, 3, 7, 8, and 13 positions are shown FIELD OF THE INVENTION in FIG. 1 as positions a-e, respectively. Adenosylcobalamin 0002 The present invention provides fortified composi can be interconverted into hydroxo- or methylcobalamin tions which include a fortifying amount of adenosylcobal depending upon cellular demand. A. E. Finkler et al., Arch. amin or hydroxycobalamin, and a food, drink, Supplement or Biochem. Biophy.s., 120, 79 (1967); C. Hall et al., J. Cell other orally ingestible diluent or carrier. Physiol., 133, 187 (1987); M. E. Rappazzo et al., J. Clin. Invest., 51, 1915 (1972) and R. Soda et al., Blood, 65,795 BACKGROUND OF THE INVENTION (1985). Adenosylcobalamin is a known compound and can 0003 Pernicious anemia, crippling neurological diseases, be chemically Synthesized using conventional techniques. ataxia and death can result from untreated Vitamin B Walker T. E. et al. (1974) Biochemistry 13:2650-5. deficiency. Cyanocobalamin is a known compound com 0007 Adenosylcobalamin, methylcobalamin and monly referred to as Vitamin B, however, cyanocobalamin hydroxycobalamin are present in minute amounts in animal does not occur naturally. Cyanocobalamin (vitamin B2) is based foods but not in vegetables. Scott, J. M. (1997) produced commercially, and is frequently used as a nutrient European J. Clinical Nutrition 51, Suppl. I, S49-S53. for humans because it is a prodrug of the metabolically Hydroxycobalamin forms when adenosylcobalamin, meth active vitamin B coenzymes. Roth, J. R. et al. (1996) Ann. ylcobalamin or Substituted cobalamins are exposed to light. Rev. Microbiol. 50:137-81. Originally isolated from liver in Many animals, including humans, require adenosylcobal 1948, vitamin B continues to be produced. In 1958, Barker amin, but do not synthesize it. Bacteria are the primary isolated a cofactor of glutamate mutase that was later Source of naturally occurring cobalamin. Commercially pro recognized to be similar to Vitamin B but missing the duced cyanocobalamin is poorly absorbed through the Stom cyano group. Weissbach, H. et al. (1960) J. Biol. Chem. 235:1462-1473. This cofactor was determined to be adeno ach and is generally administered as a Sublingual or in Sylcobalamin, and despite the discovery of adenosylcobal injection form. amin in 1958, cyanocobalamin has been consistently pro 0008 Three proteins are involved in binding to vitamin duced commercially and used therapeutically or as a B, and facilitating its absorption. Pepsin and stomach acid nutritional Supplement for more than forty years. ity act to release Vitamin B from these proteins. A protein in Saliva, haptocorrin, binds tightly to Vitamin B at low pH 0004 The naturally occurring forms of vitamin B found and may protect the molecule from acid hydrolysis and in the body include adenosylcobalamin, methylcobalamin intestinal fauna. Once in the intestine, pancreatic enzymes and hydroxycobalamin. Adenosylcobalamin and methylco release Vitamin B from haptocorrin. Intrinsic factor then balamin are coenzymes for two cobalamin-dependent binds to the Vitamin B2 until the complex reaches the ileum. enzymeS-methyl-malonyl CoA mutase and methionine Cyano-, adenosyl-, hydroxo- and methylcobalamin bind to Synthase. Because the coenzymes are not cyanocobalamin, the coenzymes are not properly designated as Vitamin B. intrinsic factor with Similar affinities. Cyanocobalamin is not Vitamin B has been historically identified as cyanocobal readily absorbed directly from the intestine, however, in part amin. Indeed, Weissbach et al. recognized a relationship because it is not as biologically active. between cyanocobalamin and Vitamin B2 coeZymes. 0009. The intrinsic factor-cobalamin complex binds to Hogenkamp, H. P. C.; B: 1948-1998. In: Chemistry and Specific receptors on the lumenal Surface of the intestine and Biochemistry of B (R. Banerjee ed.) 1999, Wiley and Sons is endocytosed. Intrinsic factor is cleaved intracellularly by New York, pp. 1-8. Chemical studies indicated that “unlike intracellular proteases, and the free vitamin B binds the Vitamin, the coenzyme lacked the cyanide ion' pp. 3-8 transcobalamin II and is released into circulation. Adenos (emphasis added). ylcobalamin in Serum is primarily bound to transcobalamin II, and Somatic cells take up Vitamin B. bound to transco 0005 Adenosylcobalamin is a necessary cofactor for balamin II through transcobalamin II receptor mediated methylmalonyl CoA mutase. This mutase is involved in endocytosis. proprionate metabolism. Methylcobalamin is required for methionine Synthase, which is necessary to recycle the folate 0010 Cobalamin is present in plasma as methylcobal cofactor 5-methyltetrahydrofolate back to tetrahydrofolate amin, adenosylcobalamin and hydroxocobalamin bound to allowing the folate cofactor to continue to participate in the the Specific proteins transcobalamins I and II. Transcobal biosynthesis of purines and pyrimidines. Methionine Syn amin I is a Storage form and mainly binds methylcobalamin, thase converts homocysteine to methionine providing whereas mentioned above transcobalamin II is the physi methyl groups needed in the methylation cycle and in the ologic B transport protein. Cobalamin coenzyme plasma synthesis of structures such as myelin. Scott, J. M. (1997) concentration is normally 200 to 750 pg/mL (150 to 550 European J. Clinical Nutrition 51, Suppl. I, S49-S53. pmol/L), which represents only about 0.1% of the total body Because adenosylcobalamin functions in the mitochondria, content of coenzymes, most of which is in the liver. Excre this coenzyme is intimately connected to energy production tion is mainly through the bile and to a lesser extent through and metabolism in general and can play critical roles in the the kidneys. The total daily loss is 2 to 15 lug. development of obesity. 0011. The recommended daily allowance of vitamin B 0006 The chemical structure of adenosylcobalamin is is 2 ug for adults, 2.2 lug for pregnant women, and 2.6 ug for shown in FIG. 1. The fundamental ring system without nursing mothers. Because cyanocobalamin (vitamin B2) is US 2005/0143340 A1 Jun. 30, 2005 poorly absorbed by itself, nutritional Supplements generally 0021 U.S. Pat. No. 5,985,339 discloses refrigeration contain 50 lug to 2 mg of cyanocobalamin. Adenosylcobal Shelf-stable ready-to-drink complete nutritional products amin and methylcobalamin can be Stored in the liver and Such as nutritional Supplements containing Vitamin B. kidneys for long periods of time and any exceSS is simply excreted. Problems absorbing vitamin B from food can 0022 U.S. Pat. No. 5,955,321 discloses a process for the also stem from any disruption in the metabolism of Vitamin preparation of a composition comprising natural Vitamin B B. Genetic abnormalities in the Vitamin B binding pro obtained from microbial cells. teins and other Vitamin B related proteins can result in 0023 U.S. Pat. No. 5,948,443 discloses methods of pro decreased absorption of Vitamin B. People who are at risk Viding micronutrient and acetylsalicylic acid Supplementa from cobalamin deficiency include those with a gastrointes tion needed for both the treatment of nutritional losses and tinal predisposition (e.g., atrophic body gastritis or previous deficiencies and the reduction of the risk of coronary heart partial gastrectomy), autoimmune disorders type 1 (insulin disease by administering a daily amount of multivitamins dependent) diabetes mellitus and thyroid disorders, those including vitamin B, minerals, and acetylsalicylic acid. receiving long term therapy with gastric acid inhibitors or 0024 U.S. Pat. No. 5,925,625 discloses a method for the biguanides, and those undergoing nitrous oxide anaesthesia. intranasal administration of a pharmaceutical composition 0012 Food cobalamin malabsorption is identified by low containing a hydroxocobalamin compound to treat cluster or low-normal Serum cobalamin levels with Symptoms of headaches. A concentrated dose of hydroxocobalamin is cobalamin deficiency Such as mild homocystinuria or meth claimed to increase its uptake in the nasal mucosa. ylmalonic aciduria and changes in mental Status. The elderly are particularly Susceptible to cobalamin deficiency because 0.025 U.S. Pat. Nos. 5,925,377 and 5,869,084 disclose normal age-related breakdown of the digestive proceSS multivitamin formulations containing Vitamin B. impairs cobalamin release in the digestive tract. For 0026 U.S. Pat. No. 5,556,644 discloses a method of example, reduced Secretion of pancreatic enzymes and improving the immunological Status of elderly perSons by hypochlorhydrosis are common age-related factors that con administering individual dosages of a nutritional Supplement tribute to food cobalamin malabsorption. In addition, there containing Vitamin B. is a decreased production of intrinsic factor, which in turn, decreases the absorption of cobalamin. Large doses of oral 0027 U.S. Pat. No. 4,976,960 discloses a food supple cyanocobalamin often override Such deficiencies. ment containing an antioxidant and cobalamin. 0013 Cyanocobalamin has historically been used to treat 0028 U.S. Pat. No. 5,964,224 discloses a method of Several disorders. Because of the poor absorption of cyano treating amyotrophic laterla Sclerosis (ALS) by parenterally cobalamin through the digestive tract, cyanocobalamin administering about 15 mg to about 100 mg per day of therapy is generally in the form of an injection or Sublingual. methylcobalamin. 0.014 Bricker Labs produces a liquid nutritional supple 0029. Because of the poor absorption of cyanocobalamin ment called B. Blast that contains 1 mg of cyanocobalamin and the Severe health problems associated with Vitamin B and 400 ug of folic acid in purified water, fructose Syrup, coenzyme deficiency, there is a Strong need in for compo natural raspberry flavor, citric acid, and 0.1% Sodium ben Sitions that can increase the levels of Vitamin B coenzyme Zoate added as a Stabilizer. Importantly, this Supplement in a host. does not contain adenosyl-cobalamin. 0030 Therefore, it is an object of this invention to 0.015 Daily administration of cyanocobalamin in combi provide methods and compositions to treat Vitamin B nation with aspirin, antioxidants and niacin is disclosed in coenzyme deficiency in a host. U.S. Pat. No. 6,121,249 as a treatment for reducing the 0031. It is another object of this invention to provide Severity of atherosclerosis, atherosclerotic central nervous methods and compositions to increase the levels of Vitamin System disease, claudication, coronary artery disease, B coenzymes in a host. homocystine related disorders, hypertension, peripheral vas cular disease, presenile dementia and/or restenosis in 0032. It is yet another object of this invention to provide humans. methods and compositions for regulating the metabolism of a host. 0016 U.S. Pat. No. 6,110,472 discloses the use of vita min B as a method for treating excessive Scalp exfoliation or Scalp hyperkeratinization. SUMMARY OF THE INVENTION 0033. The present invention provides fortified composi 0017 U.S. Pat. Nos. 6,093.425 and 6,030,650 disclose tions which include in combination: (i) a fortifying amount nutritional milk formulations containing Vitamin B12. of adenosylcobalamin or hydroxycobalamin, and (ii) a food, 0018 U.S. Pat. Nos. 5,578.336 and 5,569,477 disclose drink, Supplement or other orally ingestible diluent or car chewing gums containing Vitamin B12. rier. The present invention is based on the Surprising dis covery that adenosylcobalamin or hydroxycobalamin, pref 0019 U.S. Pat. No. 6,039,978 disclose dietary foods erably adenosylcobalamin, is absorbed significantly more enhanced with Vitamin B. efficiently than other forms of cobalamin, i.e., cyanocobal 0020 U.S. Pat. No. 6,022,853 discloses methods and amin. Adenosylcobalamin is a vitamin B coenzyme in compositions that include a morphogen in combination with which the sixth coordination position of the cobalt atom is Vitamin B which, when provided to an individual as a food linked covalently to the 5'-carbon of 5'-deoxyadenosine formulation or Supplement, is capable of enhancing tissue (FIG. 1). Hydroxycobalamin is a vitamin B coenzyme in development and viability in the individual. which the sixth coordination position of the cobalt atom is US 2005/0143340 A1 Jun. 30, 2005

linked covalently to a hydroxyl. It has been discovered that transcobalamin I, transcobalamin II or transcobalamin III, the oral administration of fortified food compositions con and most preferably intrinsic factor and/or transcobalamin taining a fortifying amount of adenosylcobalamin or II, per dose. hydroxycobalamin, preferably adenosylcobalamin, Substan tially increases levels of cobalamin in a host. Because BRIEF DESCRIPTION OF THE FIGURE adenosylcobalamin and hydroxycobalamin are light Sensi 0038 FIG. 1 is a diagram of the chemical structure of tive, in a preferred embodiment, the present invention is adenosylcobalamin. contained in opaque media or packaged or contained in opaque material. In a particular embodiment, the fortifying DETAILED DESCRIPTION OF THE amount of adenosylcobalamin and hydroxycobalamin is INVENTION optionally administered in combination with, or bound to, 0039 The fortified compositions according to the inven intrinsic factor, transcobalamin I, transcobaiamin II or tion include as an essential component a fortifying amount transcobalamin III, and most preferably intrinsic factor of adenosylcobalamin or hydroxy-cobalamin, preferably and/or transcobalamin II. adenosylcobalamin, optionally mixed with or bound to intrinsic factor, transcobalamin I, transcobalamin II or 0034. In another embodiment, the invention provides a transcobalamin III, and most preferably intrinsic factor fortified food composition which comprises in combination: and/or transcobalamin II. A fortifying amount of adenosyl (i) a fortifying amount of adenosylcobalamin or hydroxy cobalamin or hydroxycobalamin, preferably adenosylcobal cobalamin, preferably adenosylcobalamin, (ii) an orally amin, and even more preferably adenosylcobalamin mixed ingestible diluent or carrier; and (iii) at least one additional with or bound to intrinsic factor or transcobalamin II, is any Substance Selected from the group consisting of a vitamin, amount in excess of naturally occurring cobalamin or in the mineral, protein, lamino acid, carbohydrate, fat, fatty acid, food composition. Preferred amounts of total added adeno electrolyte, herb, or herbal extract. In a preferred embodi Sylcobalamin or hydroxycobalamin, preferably adenosylco ment, the fortified food composition comprises a protein, balamin optionally mixed with or bound to intrinsic factor, more specifically, adenosylcobalamin or hydroxycobalamin, transcobalamin I, transcobalamin II or transcobalamin III, preferably adenosylcobalamin, is bound to intrinsic factor, and most preferably intrinsic factor and/or transcobalamin II transcobalamin I, transcobalamin II or transcobalamin III, are between 0.1 lug to 2 mg, and more preferably, between and most preferably intrinsic factor and/or transcaobalamin 0.5 or 1 lug to 1 mg, per Serving of the fortified food II, prior to the fortification process. composition. It is understood that the fortified food compo Sitions of the present invention contain 0.1 lug to 2 mg 0035) In another embodiment, a method for increasing adenosylcobalamin or hydroxycobalamin, preferably adeno Vitamin B12 coenzyme levels in a host comprising admin Sylcobalamin optionally mixed with or bound to intrinsic istering to a host a fortified food composition containing a factor, transcobalamin I, transcobalamin II or transcobal fortifying amount of adenosylcobalamin or hydroxycobal amin III, and most preferably intrinsic factor and/or transco amin, preferably adenosylcobalamin, optionally in combi balamin II. An orally ingestible diluent or carrier may for nation with or bound to a protein Such as intrinsic factor, example include a Substance Selected from a manufactured transcobalamin I, transcobalamin II or transcobalamin III, cereal, fruit or vegetable product, a beverage or beverage and most preferably intrinsic factor and/or transcobalamin concentrate, or any inert diluent, carrier or excipient known II, in combiriation with a diluent or carrier is provided. in the pharmaceutical or food or beverage art. It is intended 0036). In yet another embodiment, a method of treating a generally that adenosylcobalamin or hydroxycobalamin, neurological disorder by orally administering adenosylco preferably adenosylcobalamin, may be used in fortified food balamin or hydroxycobalamin, preferably adenosylcobal compositions, in any of the food forms known and practiced amin, to a host is provided. The cobalamin can be optionally in the art. In one embodiment, the fortified food composition administered with or bound to intrinsic factor, transcobal is a beverage. In another embodiment, the fortified food amin I, transcobalamin II or transcobalamin III, and most composition is a food. preferably intrinsic factor and/or transcobalamin II. In a 0040. In one embodiment, the fortified food composition preferred embodiment, the neurological disease is amyo is a fortified Sports drink. By Sports drink, it is meant a trophic lateral Sclerosis. In a more preferred embodiment, beverage consumed to rehydrate and or replenish nutrients the neurological disorder is Alzheimer's Disease. Because of and energy after physical activity. Additionally, the fortified the increased absorption of adenosylcobalamin or hydroxy Sports drink can be consumed in preparation of physical cobalamin, lower doses can be used than those compared to activity. The fortified food composition of the present inven methylcobalamin or cyanocobalamin. In an alternate tion can be in the form of a Sports drink containing a embodiment, the neurological disease is multiple Sclerosis. fortifying amount of adenosylcobalamin or hydroxycobal 0037. In still another embodiment of the present inven amin, preferably adenosylcobalamin, optionally mixed with tion, a multivitamin formulation is provided containing or bound to a carrier protein, and in a nonlimiting example adenosylcobalamin or hydroxycobalamin, preferably adeno can include effective amounts of agents effective against Sylcobalamin optionally mixed with or bound to intrinsic muscle cramps together with balanced amounts of carbohy factor, transcobalamin I, transcobalamin II or transcobal drates and electrolytes. In addition, the fortified Sports drink amin III, and most preferably intrinsic factor and or transco can include ingredients to produce an acid pH. Additives to balamin II. In preferred embodiments, the multivitamin the fortified Sports drink can include fruit flavor, a preser formulation contains between 0.1 to 2 mg of adenosylco Vative and carbonation. balamin or hydroxycobalamin, preferably adenosylcobal 0041. The fortified sports drink can be manufactured and amin, optionally mixed with or bound to intrinsic factor, Sold as a single Strength beverage for direct consumption. US 2005/0143340 A1 Jun. 30, 2005

Alternatively, the fortified sports drink can be in the form of Nonlimiting examples of herbs or herbal extracts include an aqueous concentrate or Syrup to be diluted with water to Alfalfa leaf, Alfalfa Seed, Angelica root, Anise Seed, Ash yield a fortified Sports drink of desired concentration and Wanganda root, Astragalus root, Bee Pollen, Bee Propolis, taste. The fortified sports drink can also be in dry form, such Bilberries, Black Cohosh root, Black Walnut hulls, Blad as a powder or a tablet, which is dissolved in water to yield derwack, Bayberry bark, Bistort root, Blessed Thistle, Bloo the fortified food composition of this invention. droot, Blue Cohosh root, Boneset, Buckthorn bark, Buchu 0042. The fortified sports drink can be a lightly carbon leaves, Burdock root, Calendula Flower, Cascara Sagrada, ated beverage Supplementing the dietetic requirements of Chamomile flowers, Catnip leaf, Cats Claw bark, Chaparral Sugar and essential Salts in the human body which have been leaf, Chase Tree berry, Chickweed herb, Cleavers herb, depleted through vigorous physical activity. The fortified Cloves, Colts Foot leaf, Comfrey leaf, Comfrey root, Corn drink of this invention can enhance the available energy Silk, Crampbark, Cranesbill root, Cumin seed, Damiana stores and electrolytes within the body. leaf, Dandelion root, Devils Claw, Dill seed, Dill weed, Dong Quai root, Dulse, Echinacea Angustifolia, Echinacea 0043. The fortified food compositions of the present Pupurea, Elder flower, Elecampane root, Ephedra Sheep, invention further include any Vitamin in addition to adeno Eyebright herb, Eucalyptus leaf, False Unicorn root, Fennel Sylcobalamin or hydroxycobalamin, preferably adenosylco seed, Fenugreek seed, Feverfew herb, Fo-Ti Root, Garlic balamin, optionally bound to or mixed with a carrier protein. root, Gentian root, Ginger root Ginkgo Biloba, Ginseng, For example, the present fortified food compositions which Goldenseal root, Gotu Kola herb, Guarana Seeds, Grape Seed can be in the form of aqueous Solutions may include at least extract, Grapefruit Seed, Green Tea, Hawthorne berry, Hops one water-Soluble Vitamin Selected from thiamin, niacin, flowers, Horsetail, Horehound, Hydrangea root, HySSop riboflavin, pyridoxine, pantothenic acid, biotin, folic acid herb, Juniper Berries, Kava Kava root, Kelp, Kola Nut, and ascorbic acid. Alternatively or additionally, the present Lemon peel, Lemongrass, Licorice root, Lily of the Valley fortified food compositions may include at least one oil root, Lobelia herb, Lungwort lichen, Maca, Marshmallow Soluble Vitamin Selected from retinol, calciferol, menadione root, Milk Thistle seeds, Motherwort herb, Muira Puama, and tocopherol. It is understood that provitamins of the Mullein leaf, Nutmeg, Myrrh Gum, Nettle leaf, Oat Straw, identified Vitamins can be used in the present invention. A Oat Grain, Olive leaf, Orange Peel, Oregon Grape, Parsley provitamin is form of a Vitamin that is converted into a leaf, Parsley root, Passion Flower, Paul D'Arco bark, Pep biological active form of the vitamin in a host. The fortified permint leaves, Plantain herb, Prickly Ash bark, Pygeum food compositions of the present invention may also include bark, Red Clover, Red Raspberry leaf, Red Root, Rhubarb a desired mineral, including one Selected from Sodium, root, Rosemary leaf, Sage leaf, Sarsaparilla root, Saw Pal potassium, calcium, magnesium, phosphorus, chlorine and metto Berry, Schisandrae Berries, Scullcap herb, Senna Sulfur, and additionally or alternatively, at least one element pods, Stillingia root, Shave Grass herb, Sorrel herb, Shep Selected from iron, copper, manganese, iodine, cobalt, Zinc, ards Purse, Slippery Elm bark, Solomon's Seal root, Spear molybdenum, fluorine, Selenium and chromium. mint leaves, St. Johns Wortherb, Stevia leaf, Suma Thyme, 0044) The fortified food compositions of the present leaf Tribulus terestris, Tumeric, Usnea, Uva Ursi leaf, invention can contain an unsaturated fatty acids, for Valerian root, Watercress, White Willow bark, Wild Cherry example, lecithin, choline, inositol, linoleic acid, gamma bark, Wild Yam root, Wood Betony herb, Yarrow flowers, linolenic acid, dihomo-gamma-linolenic acid arachidonic Yellow Dock root, and Yohimbe bark. and eicosapentaenoic acids, known to be metabolized in the 0048. In another embodiment the invention is offered body to prostaglandins, as well as physiologically compat packaged in a vessel that protects the material from pho ible derivatives thereof, Such as Salts, esters and amides of tolyic or other breakdown, for example, opaque bottles or Such acids. opaque Wrapping. 004.5 The fortified food compositions of the present 0049. The fortified food compositions of the present invention can contain added proteins, Such as those derived invention can include any appropriate amount of a preser from gelatin, Soy or whey. In an alternate embodiment, the Vative. For example, the material can contain from about adenosylcobalamin or hydroxylcobalamin can be bound to a 100 ppm to about 1000 ppm, preferably from about 200 ppm carrier or other protein. Examples of Such proteins are more to about 650 ppm, more preferably from about 400 ppm to Specifically, intrinsic factor, transcobalamin I, transcobal about 650 ppm, of a preservative Selected from the group amin II or transcobalamin III, though most preferably intrin consisting of Sorbic acid, benzoic acid, alkali metal Salts sic factor and/or transcobalamin II, as well as physiologi thereof, and mixtures thereof. The preservative is preferably cally compatible derivatives thereof, Such as Salts, esters and Selected from the group consisting of Sorbic acid, potassium amides of Such proteins. Sorbate, Sodium Sorbate and mixtures thereof. Most pre 0046) The fortified food compositions of the present ferred is potassium Sorbate. invention can also contain a natural or Synthetic amino acid. Nonlimiting examples of amino acids include alanine, argi 0050. In one embodiment of the present invention, the nine, aspartic acid, cystine, glutamic acid, glycine, histidine, added adenosylcobalamin or hydroxycobalamin, preferably hydroxylysine, isoleucine, leucine, lysine, methionine, adenosylcobalamin, is at least 50, 60, 70 or 80% pure (i.e., omithine, phenylalanine, proline, Serine, threonine, tryp free of other forms of cobalamin). In a preferred embodi tophan, tyrosine, Valine, Ornithine, carnitine, hydroxyproline ment, the added adenosylcobalamin or hydroxycobalamin, and taurine. preferably adenosylcobalarnin, is a single optical isomer. In yet another embodiment, the added adenosylcobalamin or 0047 The fortified food compositions of the present hydroxycobalamin, preferably adenosylcobalamin, is Sub invention can contain an added herb or herbal extract. Stantially free of cyanocobalamin. Preferably, cyanocobal US 2005/0143340 A1 Jun. 30, 2005

amin is less than 20%, more preferably less than 10%, and Supplements can be used as part of a weight-loSS program, most preferred less than 5% of the added vitamin B or as part of weight-maintenance program. coenzyme. 0058. In another embodiment of the present invention, a 0051. In an alternate embodiment, the adenosylcobal method of treating cobalamin deficiency is provided com amin is in a mixture with hydroxycobalamin. In another prising administering to a host having low Vitamin B embodiment, optionally mixed with or bound adenosylco coenzyme levels a fortified food composition containing a balamin or hydroxycobalamin, preferably adenosylcobal fortifying amount of adenosylcobalamin or hydroxycobal amin, is in mixture with optionally mixed with or bound amin, preferably adenosylcobalamin, optionally mixed with cyanocobalamin. one of the carrier proteins described herein. Nonlimiting examples of hosts who can benefit from this treatment 0.052 In another embodiment, the added adenosylcobal include those with a gastrointestinal predisposition (e.g. amin or hydroxycobalamin, preferably adenosylcobalamin, atrophic body gastritis or previous partial gastrectomy),an can be either Synthetic or isolated from microbial cultures. autoimmune disorder type I (insulin-dependent) diabetes The intrinsic factor, transcobalamin I, transcobalamin II or mellitus and thyroid disorders, those receiving long term transcobalamin III can be natural or recombinant. Alterna therapy with gastric acid inhibitors or biguanides, and those tively, a variant of intrinsic factor, transcobalamin I, transco undergoing nitrous oxide anesthesia. Additionally, individu balamin II or transcobalamin III is used that retains Sub als Suffering from pernicious anemia, ataxia, or cobalamin Stantially the same biological activity but varies in Specific deficiency related neurological disorders can benefit from protein Sequence. Preferably, the adenosylcobalamin or this administration of the fortified food compositions of the hydroxycobalamin is not in the form of a microbial paste. present invention. Because of the critical role Vitamin B Instead, the adenosylcobalamin or hydroxycobalamin is coenzymes play in metabolism and methylation, patients isolated from the microbial organisms using conventional predisposed to or Suffering from Alzheimer's disease can methods known in the art including but not limited to column chromatography, which can then be optionally also benefit from the present invention. mixed with or bound to intrinsic factor, transcobalamin I, 0059) Other cobalamin related disorders that can be transcobalamin II or transcobalamin III, preferably intrinsic treated with adenosylcobalamin or hydroxycobalamin, pref factor and/or transcobalamin II prior to fortification. erably adenosylcobalamin fortified food, drink or Supple ments include cblF-lySOSomal accumulation of free cobal 0053. In yet another embodiment, the fortified food com amin; cblC and cblD-combined homocystinuria and position is a cereal. Cereals can be in the form of ready-to methylmalonic aciduria; cblA, cblA', and cblB-defective eat cereals, cereal bars or granola bars. Alternatively, the adenosylcobalamin Synthesis, and cblE and cblG-methylco cereal can require preparation including cooking. balamin deficiency. 0054. In another embodiment, the fortified food compo 0060. In another embodiment, a method for treating a Sition is a Snack food. In various embodiments, the Snack neurological disorder in a host is provided comprising orally food can be in the form of ready-to-eat packages or require administering an effective amount of adenosylcobalamin or preparation including cooking. Examples of Snack foods hydroxycobalamin, preferably adenosylcobalamin to a host. include, but are not limited to popcom, pretzels, nuts, Such In one embodiment, the neurological disorder is amyo as peanuts, Sunflower nuts and pistachio nuts, potato chips, trophic lateral Sclerosis. Amyotrophic lateral Sclerosis is a crackers, fries, candy, pudding and popsicles. progressive disease affecting upper and lower motor neurons 0055. In still another embodiment, the fortified food in the brain and the Spinal cord. In another embodiment, the composition is a gelled confection. In one embodiment, a neurological disorder is multiple Sclerosis. Because of the gelled confection can consist primarily of Sugars and a fruit increased absorption of adenosylcobalamin or hydroxyco base. The gelled confection can be packaged in sheets or in balamin compared to cyano- and methylcobalamin, and due discrete units. to the importance of cobalamin to mylenation, high doses are not required. In preferred embodiments, adenosylcobal 0056. In another embodiment, the fortified food compo amin or hydroxycobalamin, preferably adenosylcobalamin, Sition is a chewing confection. In one embodiment, a chew is administered orally on a daily basis in a dose of 0.1 lug to ing confection can consist primarily of a gum base, option 10 mg, more preferably in a dose of 1 to 5 mg, and most ally flavored with Sugar, natural or artificial flavors or fruit preferably in a dose of 1 to 2 mg. juice. The chewing confection can be packaged in sheets or in discrete units. 0061. In still another embodiment of the present inven tion, a multivitamin formulation containing adenosylcobal 0057 The fortified food compositions of the present amin or hydroxycobalamin, preferably adenosylcobalamin, invention can be in the form of fortified bread products, is provided. In preferred embodiments, isolated adenosyl cakes, donuts and cookies. The fortified food compositions cobalamin or hydroxycobalamin, preferably adenosylcobal can also be in the form of breakfast foods including but not amin, can be from 0.1 lug to 2 mg per dose. Additional limited to breakfast bars, Waffles and pastries. Additionally, Vitamins can include at least one water-Soluble Vitamin the fortified food compositions of the present invention can Selected from thiamin, niacin, riboflavin, pyridoxine, pan be health bars or energy bars. Health bars or energy bars can tothenic acid, biotin, folic acid and ascorbic acid. Alterna contain carbohydrates, Sugars and other nutrients to replen tively or additionally, the present multivitamin formulation ish depleted body Stores or to increase body Stores in can include at least one oil-Soluble vitamin Selected from preparation of physical activity. The fortified food compo retinol, calciferol, menadione and tocopherol. In preferred Sitions can also be formulated to provide a low calorie embodiments, the multivitamin formulation also can contain dietary Supplement. Such fortified low calorie dietary folic acid, preferably between 100 to 400 tug of folic acid. It US 2005/0143340 A1 Jun. 30, 2005

is understood that provitamins of the identified Vitamins can mers 22:547-556, 1983), or poly-D-(-)-3-hydroxybutyric be used in the present invention. The multivitamin formu acid (EP 133,988). Sustained release compositions also lation of the present invention can also include an added include one or more liposomally entrapped optionally mixed mineral, for example, Sodium, potassium, calcium, magne with or bound adenosylcobalamin or hydroxycobalamin, sium, phosphorus, chlorine and Sulfur, and additionally or preferably adenosylcobalamin. Such compositions are pre alternatively, at least one element Selected from iron, copper, pared by methods known per se, e.g., as taught by Epstein manganese, iodine, cobalt, Zinc, molybdenum, fluorine, et al. Proc. Natl. Acad. Sci. USA 82:3688-3692, 1985. Selenium and chromium. Any desired amount can be used, Ordinarily, the liposomes are of the small (200-800 A) for example, the additional Vitamins, minerals, folic acid and unilamellar type in which the lipid content is greater than elements can be from 5% to 110% of the Recommended about 30 mol % cholesterol, the selected proportion being Daily Allowance or multiples of the Recommended Daily adjusted for the optimal therapy. Allowance. The multivitamin formulations can be used for 0070 A variety of techniques to produce microparticles prenatal Vitamin formulations as well as adult Vitamin have been described in the prior art. For example, United formulation. Kingdom Patent Application No. 2,234,896 to Bodmer et al. describes a method of forming microparticles by mixing a Definitions and Use of Terms Solution of the polymer dissolved in an appropriate Solvent 0.062. As used herein, “fortifying amount” of an added with a Solution of a drug. Microparticle formation is then Substance refers to an amount exceeding any naturally induced by the addition of a phase inducing agent. European occurring amount of that Substance found in the material to Patent Application 0 330 180 to Hyon et al. describes a which the fortifying amount is added. process for preparing polylactic acid-type microparticles by adding a Solution of a drug and a polymer in a mixed Solvent 0.063. The term “vitamin B” refers to cyanocobalamin. to a phase inducing agent and evaporating the original 0064. As used herein, the term “vitamin B coenzyme” Solvent microparticle formation. Other examples of pro refers to adenosylcobalamin, methylcobalamin or both. ceSSes for preparing microparticles by phase Separation technique have been described in U.S. Pat. Nos. 4,732,763 0065. As used herein, the term “host” refers to an animal to Beck et al. and 4,897.268 to Tice et al. and by Ruiz et al. including humans that utilize Vitamin B coenzymes. in the International Journal of Pharmaceutics (1989) 49:69 0.066 As used herein, the term “and/or” for example in 77 and in Pharmaceutical Research (1990) 9:928-934. reference to the phrase “intrinsic factor and/or transcobal 0071. The fortified compositions may be administered in amin II” refers to cobalamin compositions bound to intrinsic combination with a pharmaceutically acceptable vehicle factor Separately, transcobalamin II Separately, or a combi Such as an inert diluent or an assimilable edible carrier. They nation of Separately bound intrinsic factor and transcobala may be enclosed in hard or Soft shell gelatin capsules, nin II. compressed into tablets or incorporated directly with the food of the patient's diet. For oral therapeutic administra Fortifying Dosage Forms tion, the Substance may be combined with one or more excipients and used in the form of ingestible tablets, buccal 0067. The present invention provides fortified foods, tablets, troches, capsules, elixirs, Suspensions, Syrups, drinks, Supplements and other compositions containing wafers, and the like. Such compositions and preparations optionally mixed with or bound adenosylcobalamin or should optionally contain at least 0.1% of the substance. The hydroxycobalamin, preferably adenosylcobalamin. The percentage of the compositions and preparations may, of cobalamin fortified materials can be administered orally to any host in need thereof, including a mammalian host Such course, be varied and may conveniently be between about 2 as a human. Alternatively, the cobalamin fortified materials to about 60% of the weight of a given unit dosage form. The can be dissolved in any appropriate liquid, Such as water or amount of Substance in Such therapeutically useful compo an emulsifier, and administered by the Spraying onto of a sitions is such that an effective dosage level will be obtained. food ingredient, for example by Spray bottle, destined for 0072 Tablets, troches, pills, capsules and the like may consumption after the food ingredient is produced. also contain the following: binderS Such as gum tragacanth, 0068 The fortified compositions herein are also suitably acacia, corn Starch or gelatin; excipients Such as dicalcium administered by Sustained release Systems. The Sustained phosphate, a disintegrating agent Such as corn Starch, potato release Systems can be tailored for administration according Starch, alginic acid and the like; a lubricant Such as magne to any one of the proposed administration regimes. Slow or sium Stearate; and a Sweetening agent Such as Sucrose, extended-release delivery Systems, including any of a num fructose, lactose or aspartame or a flavoring agent Such as ber of biopolymers (biological-based Systems), Systems peppermint, oil of wintergreen, or cherry flavoring may be employing liposomes, and polymeric delivery Systems, can added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid be utilized with the compositions described herein to pro carrier, Such as a vegetable oil or a polyethylene glycol. vide a continuous or long term Source of therapeutic com Various other materials may be present as coatings or to pound. otherwise modify the physical form of the Solid unit dosage 0069 Suitable examples of Sustained release composi form. For instance, tablets, pills or capsules may be coated tions include Semi-permeable polymer matrices in the form with gelatin, wax, shellac or Sugar and the like. A Syrup or of shaped articles, e.g., films, microcapsules or micro elixir may contain the active compound, Sucrose or fructose Spheres. Sustained release matrices include, for example, as a Sweetening agent, methyl and propylparabens as pre polylactides (U.S. Pat. No. 3,773.919), copolymers of L-glu Servatives, a dye and flavoring Such as cherry or orange tarnic acid and Y-ethyl-L-glutamate (Sidman et al., Biopoly flavor. Of course, any material used in preparing any unit US 2005/0143340 A1 Jun. 30, 2005 dosage form should be pharmaceutically acceptable and Example 1 Substantially non-toxic in the amounts employed. In addi tion, the Substance may be incorporated into Sustained Fortified Fruit Juice release preparations and devices. 0080. In one embodiment of the present invention, the 0.073 Sublingual tablets are designed to dissolve very fortified food compositions can contain fruit juice, which rapidly. Examples of Such formulations include ergotamine can provide flavor and nutrition. In a preferred embodiment, tartrate, isosorbide dinitrate, isoproterenol HCl. The formu the amount of isolated or bound adenosylcobalamin or lation of these tablets contain, in addition to the drug, a hydroxycobalamin, preferably adenosylcobalamin, in the limited number of Soluble excipients, usually lactose and fortified fruit juice is between 0.1 lug to 2 mg per Serving. powdered Sucrose, but occasionally dextrose and mannitol. The fruit juice in the fortified food compositions can be any The process of making Sublingual tablets involves moisten citrus juice, non-citrus juice or mixture thereof, which are ing the blended powder components with an alcohol-water known in the art. Examples of Such fruit juices include, but Solvent System containing approximately 60% alcohol and are not limited to, non-citrus juices Such as applejuice, grape 40% water. juice, pear juice, nectarine juice, currant juice, raspberry 0.074. In addition to the fortified food compositions, the juice, gooseberry juice, blackberry juice, blueberry juice, prototype formulation for Sublingual tablets may contain a Strawberry juice, custard-apple juice, pomegranate juice, binder such as povidone or HPMC, diluents such as lactose, guava juice, kiwi juice, mango juice, papaya juice, Water mannitol, Starch or cellulose, a disintegrant Such as prege melon juice, cantaloupe juice, cherry juice, cranberry juice, latinized or modified Starch, lubricants Such as magnesium pineapple juice, peach juice, apricot juice, plum juice and Stearate, Stearic acid or hydrogenated vegetable oil, a Sweet mixtures thereof, and citrus juices Such as orange juice, ener Such as Saccharin or Sucrose and Suitable flavoring and lemon juice, lime juice, grapefruit juice, tangerine juice and coloring agents. mixtures thereof. Other fruit juices, fruit flavored juices, and nonfruit juices Such as Vegetable or botanical juices, can be 0075 An effective dosages of the adenosylcobalamin or used as the juice component of the fortified food composi hydroxy-cobalamin can be used for all of the embodiments tions of the present invention. described herein. Dosages can be determined routinely by any number of methods, including by comparing the in vitro 0081 Additionally, other vitamin, mineral, protein, activity, and in vivo activity in animal models. Methods for amino acid, carbohydrate, fat, fatty acid, electrolyte, herb or the extrapolation of effective dosages in mice, and other herbal extract can be used. animals, to humans are known to the art; for example, See 0082 In a preferred embodiment, adenosylcobalamin or U.S. Pat. No. 4,938,949. The amount of the Substance hydroxycobalamin is bound to a protein, more specifically, required for use in treatment will vary not only with the intrinsic factor, transcobalamin I, transcobalamin II or nature of the condition being treated and the age and transcobalamin III. Specifically, adenosylcobalamin or condition of the patient and will be ultimately at the discre hydroxycobalamin bound to intrinsic factor and/or transco tion of the attendant physician or clinician. balamin II can be used to fortify the fruit juice. 0.076. In general, a suitable dose will be in the range of from about 0.1 lug to 2 mg. The Substance is conveniently Example 2 administered in unit dosage form. For example, the fortified food composition can contain 0.1 lug to 2 mg, conveniently Fortified Beverages 1 ug to 2 mg, most conveniently, 1 to 2 mg of optionally mixed with or bound adenosylcobalamin or hydroxycobal 0083. In one embodiment, the fortified food compositions amin, preferably adenosylcobalamin, per unit dosage form. of the present invention can be noncarbonated beverage compositions, and typically will, contain an artificial or 0077. The substance may conveniently be presented in a natural, caloric or noncaloric, Sweetener. Carbohydrate Single dose or as divided doses administered at appropriate Sweeteners are preferred, more preferably mono- and or intervals, for example, as two, three, four or more Sub-doses di-Saccharide Sugars. In preferred embodiments, the fortified per day. beverages can contain between 0.1 lug to 2 mg of isolated 0078 By the term “effective amount” of a compound as adenosylcobalamin per Serving. provided herein is meant a nontoxic but Sufficient amount of 0084. In another embodiment, the fortified beverage the compound to provide the desired effect. As will be compositions can contain a carbonating agent. pointed out below, the exact amount required will vary from Subject to Subject, depending on the Species, age, and 0085 U.S. Pat. No. 6,126,980 to Smith et al. discloses general condition of the Subject, the type and Severity of the beverages with increased microbial Stability and processes condition that is being treated, the particular compound for preparing them. The fortified beverages of the present invention can be prepared using Similar methods. Briefly, the used, its mode of administration, and the like. Thus, it is not fortified beverage compositions of the present invention will possible to Specify an exact “effective amount.” However, an typically comprise from about 0.1% to about 20%, more appropriate effective amount may be determined by one of preferably from about 5% to about 15%, Sugar Solids by ordinary skill in the art using only routine experimentation. weight of the beverage products. Suitable Sweetener Sugars EXAMPLES include maltose, Sucrose, glucose, fructose, invert Sugars and mixtures thereof. These Sugars can be incorporated into 0079 The following examples are given for the purpose the beverage products in Solid or liquid form but are typi of illustrating various embodiments of the invention and are cally, and preferably, incorporated as a Syrup, more prefer not meant to limit the present invention in any fashion. ably as a concentrated Syrup Such as high fructose corn US 2005/0143340 A1 Jun. 30, 2005

Syrup. For purposes of preparing the fortified beverage milk, that may contain a combination of whole milk, skim compositions of the present invention, these optional Sweet milk, condensed milk, dry milk (dry milk Solids non-fat or, eners can be provided to Some extent by other components equivalently, “MSNF), grade A whey, cream and/or such of the fortified beverage products Such as the fruit juice other milk fraction ingredients as buttermilk, whey, lactose, component, optional flavorants, and So forth. lactalbumins, lactoglobulins, or whey modified by partial or 0.086 Preferred carbohydrate Sweeteners for use in the complete removal of lactose and/or minerals, other dairy fortified beverage compositions are Sucrose, fructose and ingredients to increase the nonfat Solids content, which are mixtures thereof. Fructose can be obtained or provided as blended to provide the desired fat and solids content. While liquid fructose, high fructose corn Syrup, dry fructose or not preferred, the milk base can include a filled milk fructose Syrup, but is preferably provided as high fructose component, i.e., a milk ingredient having a portion Supplied corn syrup. High fructose corn syrup (HFCS) is commer by a non-milk ingredient, e.g., oil or Soybean milk. cially available as HFCS-42, HFCS-55 and HFCS-90, which comprise 42%, 55% and 90%, respectively, by weight of the 0094. Although the present invention is discussed in terms of fermented bovine milk products Such as yogurt, one Sugar Solids therein as fructose. skilled in the art will appreciate that the present invention is 0.087 Optional artificial or noncaloric Sweeteners for use also Suitable for use in a wide variety of thickened dairy in the fortified beverage compositions include, for example, products, particularly fermented dairy products Such as kefir, Saccharin, cyclamates, Sucrose, acetoSulfam, L-aspartyl-L- Sour cream, butter and the like. phenylalanine lower alkyl ester Sweeteners (e.g., aspar tame), L-aspartyl-D-alanine amides disclosed in U.S. Pat. 0095 Also, while bovine milk is preferred, other milks No. 4,411,925 to Brennan et al., L-aspartyl-D-serine amides can be used in Substitution for bovine milk whether in whole disclosed in U.S. Pat. No. 4,399,163 to Brennan et al., or in part, e.g., goat, sheep or equine milk. Milk alternatives L-aspartyl-L-1-hydroxymethyl-allaneamide Sweeteners dis can also be used Such as Soybean based beverages. closed in U.S. Pat. No. 4,338,346 to Brand, L-aspartyl-1- 0096 Conveniently, the raw milk and Sweeteners (such hydroxyethylakaneamide Sweeteners disclosed in U.S. Pat. as fructose, corn Syrup, Sucrose) can be blended in a mix No. 4,423,029 to Rizzi, and L-aspartyl-D-phenylglycine tank and Stored in a milk silo. Stabilizers and thickenerS Such ester and amide Sweeteners. A preferred Sweetener is aspar as Starch, gelatin, pectin, agar and carrageenan may also be tame. added if desired. The minor dry ingredients are combined 0088. The fortified beverage compositions herein can with the Sweetened milk to form the milk base conveniently further comprise any other ingredient or ingredients typi in a separate mixing vessel. cally used as optional beverage ingredients. Such optional ingredients include flavorants, preservatives, colorants and 0097. The milk base is then homogenized in a conven So forth. tional homogenizer to disperse evenly the added materials and the fat component Supplied by various ingredients 0089. The fortified beverage compositions can further thereby forming an homogenized milk base. If desired, the comprise any amount, including from 1 to about 110% of the milk base can be warmed prior to homogenization from U.S. Recommended Daily Allowance (RDA) of vitamins typical milk storage temperatures of about 5 C. to tempera and minerals other than adenosylcobalamin or hydroxyco tures of about 65° to 75° C. balamin. Nonlimiting examples include Vitamin A, includ ing its provitamins Such as beta carotene, and ascorbic acid. 0098. This homogenized milk base is then pasteurized, typically by heating for times and temperatures effective to 0090. Additionally, other vitamin, mineral, protein, accomplish pasteurization to form a pasteurized milk base. amino acid, carbohydrate, fat, fatty acid, electrolyte, herb or AS is well known, the milk base can be heated to lower herbal extract can be used. temperatures for extended times or alternately to higher 0.091 In a preferred embodiment, adenosylcobalamin or temperatures for shorter times. Intermediate temperatures hydroxycobalamin used to fortify the beverage is mixed for intermediate times can also be employed. Other pasteur with or bound to a protein, more specifically, intrinsic factor, ization techniques can be practiced (e.g., light pulse, ultra transcobalamin I, transcobalamin II or transcobalamin III. high pressure, etc.) if effective and economical. In certain Specifically, adenosylcobalamin or hydroxycobalamin commercial practices, the Sequence of the homogenization bound to intrinsic factor and/or transcobalamin II can be and pasteurization Steps can be reversed. used to fortify the beverage. 0099. The homogenized and pasteurized base is then Example 3 brought to incubation temperature. The homogenized and pasteurized milk blend is then inoculated with a desired Fortified Dairy Products culture. Usually, a combination of lactobacillus bulgaricus 0092. In yet another embodiment, the fortified food com and Streptococcus thermophilus bacteria is added to begin position may be a dairy based product Such as a milk the fermentation process. Fermentation is quiescently con beverage, a confectionery product, ice cream, or yogurt. In tinued until the pH of the milk blend reaches approximately preferred embodiments, 0.1 lug to 2 mg per Serving of 4.4 to 4.6 to form the yogurt base. Depending upon tem isolated or bound adenosylcobalamin or hydroxycobalamin, perature and amount of culture added, this may take from preferably adenosyl-cobalamin, is added to the dairy based about three to about 14 hours. It is important that the mixture product. not be agitated during the fermentation process to allow proper curd formation. When the proper pH has been 0093 U.S. Pat. No. 5,820,903 discloses methods for reached, the yogurt is cooled to arrest further growth and any producing yogurt. Briefly, yogurt can be prepared with raw further drop in the pH. US 2005/0143340 A1 Jun. 30, 2005

0100. The particular fermentation endpoint pH can vary granular cereal can be sprayed or Sprinkled with liquid milk modestly. Typically, the endpoint pH can range from about in which isolated adenosylcobalamin, Sugar, Salt, fruit juice 4.2 to 4.6, preferably about 4.45 to 4.55. puree, and/or flavoring materials are dissolved, whereby the 0101 The person of ordinary skilled in the art will mixture is absorbed by the oat flakes and evenly distributed appreciate that the adenosylcobalamin fortification methods throughout the body of the flakes. Alternatively, isolated or herein rely upon post fermentation rather than pre-fermen bound adenosylcobalamin or hydroxycobalamin dissolved tation addition. In preferred embodiments, optionally mixed in any appropriate liquid, Such as water or an emulsifier, can with or bound adenosylcobalamin or hydroxylcobalamin, be sprayed on the cereal ingredient after the cereal ingredi preferably adenosyl-cobalamin, can be added to the yogurt ent is produced. in amounts between 0.1 lug to 2 mg per Serving. 0107 Cream, butterfat or cream Substitute may be added to the milk to improve the flavor and the texture of the 0102 Although a live yogurt product is preferred, the product. The cream or dry cream Substitute may be mixed present invention can also be used in yogurt-based foods as with the milk or it may be added to the cereal in a distinguished from a yogurt product. For example, a shelf conventional mixer after the milk containing the other Stable yogurt-based product is prepared by heat treating a additives has been added. If a dry cream Substitute is used, yogurt to inactivate the culture and packaging aseptically. In it may be dusted onto the cereal while the mixer is operating. this variation, the pH of the yogurt based product can be The amount of milk added to the cereal is determined by the adjusted for taste or for compatibility with other ingredients. desired crunchiness of the resulting product, i.e., if a rela For example, the pH can be adjusted upwards Substantially tively small amount of milk is used and little fruit is added, for a chocolate flavored yogurt based product. the product will be relatively soft and water absorptive and 0103) Additionally, other vitamins, minerals, proteins, not crunchy, or if a higher proportion of milk with fruit is amino acids, carbohydrates, fats, fatty acids, electrolytes, used to wet the cereal, which is thereafter dried, it is crunchy. herbs or herbal extracts can be used in conjunction with the fortified dairy product. Example 5 0104. In a preferred embodiment, adenosylcobalamin or Fortified Snack Food hydroxycobalamin is bound to a protein, more specifically, 0108. In another embodiment, the present invention dis intrinsic factor, transcobalamin I, transcobalamin II or closes a fortified food composition consisting of a Snack transcobalamin III prior to fortification of the dairy product. food containing a fortifying amount of isolated or bound Specifically, adenosylcobalamin or hydroxycobalamin is adenosylcobalamin or hydroxycobalamin. Snack foods bound to intrinsic factor and or transcobalamin II to fortify include, but are not limited to popcorn, pretzels, nuts, Such the dairy product. as peanuts, Sunflower nuts and pistachio nuts, potato chips, crackers, fries, candy, pudding and popsicles. In preferred Example 4 embodiments, 0.1 lug to 2 mg of isolated or bound adenos ylcobalamin or hydroxycobalamin is added per Serving to Fortified Cereal the fortified cereal food composition. 0105. In another embodiment, the present invention dis 0109 Artificial or natural flavorings, cream, butterfat or closes a fortified food composition consisting of a cereal cream Substitute may be added to the Snack product to ingredient containing a fortifying amount of optionally improve the flavor and the texture. The artificial or natural mixed with or bound adenosylcobalamin or hydroxycobal flavorings, cream, butterfat, cream Substitute or dry cream amin. Other products, Such as Waffles, Snack bars, toaster Substitute may be added to the Snack product in a conven pastries, and pastry products, can be fortified in the same tional mixer after the other additives has been added. If a dry manner with optionally mixed with or bound adenosylco cream Substitute is used, it may be dusted onto the Snack balamin or hydroxycobalamin, either alone or in combina product while the mixer is operating. The amount of artifi tion with an additional Vitamins, minerals, proteins, amino cial or natural flavorings, cream, butterfat, cream Substitute acids, carbohydrates, fats, fatty acids, electrolytes, herbs or or dry cream Substitute added to the Snack product is herbal extracts. Cereal ingredients include plain or puffed determined by the desired crunchiness and flavor of the wheat, rice, oat, corn, barley, rye, millet, Sorghum, amaranth resulting product, i.e., if a relatively Small amount of milk is Seed and mixtures of the above can also be used in the used and little fruit is added, the product will be relatively preparation of the fortified food compositions. In preferred Soft and water absorptive and not crunchy, or if a higher embodiments, 0.1 lug to 2 mg of isolated or bound adenos proportion of milk with fruit is used to wet the Snack ylcobalamin or hydroxycobalamin is added per Serving to product, which is thereafter dried, it is crunchy. the fortified cereal food composition. Example 6 0106. In another embodiment, the fortified food compo sition is a cereal product. U.S. Pat. No. 3,494,769 describes Fortified Confections a breakfast cereal Suitable for use as cold cereal by the addition of milk, or as a hot cereal by the addition of hot 0110. In another embodiment, the present invention pro water. The cereal is prepared by heating rolled oats to cook vides fortified Sweetened confections. In preferred embodi the Starch and protein contained therein, applying liquid ments, 0.1 g to 2 mg per Serving of isolated or bound milk in Sufficient quantity only to wet the oats and to adenosylcobalamin or hydroxycobalamin is added to the distribute it evenly throughout the oat product, and then Sweetened products. drying the wet product to crispness, producing a crunchy 0111 U.S. Pat. No. 6,077.557 discloses calcium fortified product. During the manufacturing process, the flaky or gelled Sweetened fruit products. Similar compositions and US 2005/0143340 A1 Jun. 30, 2005 methods are applicable to isolated or bound adenosylcobal apple, lemon, Orange, peach, pear, lime, banana, grape, amin or hydroxycobalamin fortified Sweetened confections. mango, apple, tomato, blackberry, plum, watermelon, blue Briefly, a principal essential component of the present inven berry, raspberry, Strawberry, current, cherry, cranberry, and tion food products is one or more nutritive carbohydrate mixtures thereof. Preferred fruits are selected from the group Sweeteners or Sugars. The present confections essentially consisting of apples, Strawberries, cherries, pears, blueber comprise about 60% to about 85% of Such nutritive carbo ries, raspberries, grapes, oranges and mixtures thereof Most hydrate Sweeteners, preferably about 60% to about 75%, and highly preferred for use herein are grapes, Strawberries, for best results about 65% to about 70%. Such sugars also pears, oranges and cherries. influence the texture and structure of the present products. 0112 The term “nutritive carbohydrate Sweetening 0118 Fresh fruit is preferable and useful for preparing the agent' is used herein to mean those typical purified Sweet products herein. However, previously frozen fruit, canned ening agents conventionally used in food products. Of fruit, partially dehydrated fruit or rehydrated fruit, as well as course, the present nutritive carbohydrate-Sweetening agents frozen juices, concentrates, nectars, powderS or frozen juice are to be distinguished from non-nutritive carbohydrate high pulps are also Suitable. potency Sweetening agents Such as Saccharine, cyclamate, and the like. Additionally, the present nutritive carbohy 0119). While this embodiment is primarily directed drate-Sweetening agents are to be distinguished from Such towards fortified fruit containing products, the skilled artisan protein-based Sweetening agents as aspartame, thaumatin will appreciate that the present invention is equivalently and monellin. applicable to all edible plant Solids, especially ordinary 0113 Suitable materials for use as nutritive carbohydrate garden-variety vegetables. The Sugars, flavors, acids, pecti Sweetening agents are well known in the art. Examples of naceous or cellulosic fibers and ash of which plant Solids are Sweetening agents include both monosaccharide and disac typically comprised are intended to be included within the charide SugarS Such as Sucrose, invert Sugar, dextrose, lac term edible plant solids. However, “edible plant solids” is tose, honey, maltose, fructose, maple Syrup and corn Syrup not intended to include Such Starch fractions as wheat or or corn syrup Solids. Preferred nutritive carbohydrate Sweet other cereal flours nor oleaginous materials. Such Soybean ening agents are those Selected from the group consisting of oil. The present fruit solids can be wholly or partially Sucrose, glucose, fructose, corn Syrup Solids, and honey. replaced with equivalent amounts of ordinary garden Veg Highly preferred nutritive carbohydrate Sweetening agents etable Solids. are those selected from the group consisting of sucrose, corn 0120 Fruit juice solids from fruit sources such as grape Syrup Solids, and fructose. Of course, mixtures of the above juice, applejuice and pearijuice are preferred. If present, Such noted materials are contemplated herein. juice solids can constitute about 0.1 to about 70% of the 0114. In a preferred embodiment, the ratio of monosac finished fortified fruit Snack products herein. charide to disaccharide SweetenerS is controlled So as to minimize the development of unwanted properties in the 0121. In even more preferred embodiments, the present finished food product Over Storage Such as the development compositions comprise from about 5 to 100% (dry weight of crystals. To that end, the ratio can be and preferably does basis) of the nutritive carbohydrate Sweetener component of range from about 0.5:1 to about 1.8:1, and more preferably, fruit or plant solids. Preferably, the fruit solids are present at about 0.7:1 to about 1.5:1. from about 5 to 25% of the Sweetener component. More preferably, the fruit solids include about 5 to 15% of the 0115) In preferred embodiments, the fortified Sweetened nutritive carbohydrate Sweetener component. confections herein are fruit products. In Such preferred embodiments, the fortified Sweetened confections are further 0122) If desired, the present fortified Sweetened confec essentially characterized by having at least a portion of the tions can additionally comprise Supplemental high potency nutritive carbohydrate Sweeteners as being provided by or SweetenerS Such as Saccharine, aspartame, thaumatin, potas from fruit sources or fruit Solids. The fruit Solids can be sium acetylsulfame and mixtures thereof. Other suitable derived from fruit purees prepared from whole fruit flesh or high potency Sweeteners that become permitted for use or if Such purees have been partially dehydrated, fruit paste. commercially available from time to time can also be used. The term “puree' has been used in the art to refer to both heat treated, e.g., boiled and untreated food pulp. AS used 0123 Suitable gelling agents are known in the art and the herein, however, “puree' is meant to refer both to heat and skilled artisan will not have difficulty in selecting suitable unheat-treated whole fruit pieces, which have been mechani gelling agent(s) for use herein. Gelling agents are distin cally transformed into fluids. Thus, the present comminuted guishable from mere thickening agents. Exemplary gelling fruit material can be distinguished from discrete individual agents include gelatin, gellan gum, carbohydrate gel forming pieces of intact fruit flesh. polymers (such as pectin, gel forming starches, dextran, 0116. Both unseeded and, preferably, deseeded purees agar, and mixtures thereof), and mixtures thereof and can be used. Fruit puree generally contains about 35 to 90% wherein the gel is free of alginates. Among the gel forming moisture. Other edible fruit portions, Such as fruit pulp can carbohydrate polymer gel forming ingredients, pectin and also Supply the fruit Solids component. Fruit pulp is the gel forming Starches are preferred. Preferred for use herein material remaining after fruit juices have been removed is gelatin or pectin. from fruit puree. Additionally useful herein for Supplying 0.124. It will be appreciated that the fruit solids, if the fruit Solids are various fruit juices whether Single employed, will additionally provide Some native amount of Strength or concentrated. pectin. Preferably, the total pectin (including both the native 0.117) Fruit materials from any fruit can be used herein. pectin associated with the fruit Solids and added pure pectin) Examples of Such fruits useful herein include apricot, pine content ranges from about 0.9% to about 2%. US 2005/0143340 A1 Jun. 30, 2005

Example 7 intrinsic factor, transcobalamin I, transcobalamin II and/or transcobalamin III, Fortified Chewing Gum wherein the food composition is Selected from the group 0.125. In another embodiment, the present invention pro consisting of a cereal, a gelled confection consisting vides fortified gum products. In preferred embodiments, 0.1 primarily of Sugars and a fruit base, a chewing confec tug to 2 mg per Serving of isolated or bound adenosylcobal tion, a cereal bar or granola bar, a Supplement, a fruit amin or hydroxycobalamin is added to the gum products. juice, a Vegetable juice, a botanical juice, popcorn, pretzels, nuts, potato chips, and fries. 0.126 Optionally, the gum products comprise one or more 2. A fortified food composition according to claim 1, nutritive carbohydrate SweetenerS or Sugars. In one non wherein the adenosylcobalamin is bound to intrinsic factor limiting embodiment, the present gum products essentially or transcobalamin II. comprise about 60% to about 85% of Such nutritive carbo 3. A fortified food composition, comprising a fortifying hydrate Sweeteners, preferably about 60% to about 75%, and amount of adenosylcobalamin, mixed with or bound to for best results about 65% to about 70%. Such sugars also intrinsic factor, transcobalamin I, transcobalamin II and/or influence the texture and structure of the present products. transcobalamin III, wherein the food includes a Substance 0127 Suitable materials for use as nutritive carbohydrate Selected from the group consisting of a manufactured cereal, Sweetening agents are well known in the art. Examples of a fruit or vegetable product, a beverage or beverage con Sweetening agents include both monosaccharide and disac centrate, a ground meat product or a vegetable analog charide SugarS Such as Sucrose, invert Sugar, dextrose, lac thereof. tose, honey, maltose, fructose, maple Syrup and corn Syrup 4. A fortified food composition according to claim 1, or corn syrup Solids. Preferred nutritive carbohydrate Sweet which is further fortified with at least one additional ingre ening agents are those Selected from the group consisting of dient Selected from the group consisting of thiamin, ribo Sucrose, glucose, fructose, corn Syrup Solids, and honey. flavin, niacin, pyridoxine, pantothenic acid, biotin, ascorbic Highly preferred nutritive carbohydrate Sweetening agents acid, retinol, calciferol, tocopherol, menadione, potassium, are those Selected from the group consisting of Sucrose, corn calcium, phosphorus, magnesium, chlorine, Sulfur, iron, Syrup Solids, and fructose. Of course, mixtures of the above copper, iodine, manganese, cobalt, Zinc molybdenum, fluo noted materials are contemplated herein. rine, Selenium, chromium, unsaturated fatty acids, an herb or herbal extract, and folic acid. 0128. In a preferred embodiment, the ratio of monosac 5. A method for increasing vitamin B coenzyme levels charide to disaccharide SweetenerS is controlled So as to in a host comprising administering to the host a fortified minimize the development of unwanted properties in the food composition comprising a fortifying amount of adeno finished food product Over Storage Such as the development Sylcobalamin, mixed with or bound to intrinsic factor, of crystals. To that end, the ratio can be and preferably does transcobalamin I, transcobalamin II and/or transcobalamin range from about 0.5:1 to about 1.8:1, and more preferably, III, about 0.7:1 to about 1.5:1. wherein the food composition is Selected from the group 0129. In even more preferred embodiments, the present consisting of a cereal, a gelled confection consisting compositions essentially comprise from about 5 to 100% primarily of Sugars and a fruit base, a chewing confec (dry weight basis) of the nutritive carbohydrate Sweetener tion, a cereal bar or granola bar, a Supplement, a fruit component of fruit or plant solids. Preferably, the fruit solids juice, a Vegetable juice, a botanical juice, popcorn, are present at from about 5 to 25% of the Sweetener pretzels, nuts, potato chips. and fries. component. More preferably, the fruit Solids are comprise 6. The method of claim 5, wherein the adenosylcobalamin about 5 to 15% of the nutritive carbohydrate Sweetener is bound to intrinsic factor and/or transcobalamin II. component. 7. The fortified food composition of claim 1 or 2, wherein 0.130) If desired, the present fortified gum products can the food composition is contained within an opaque media, additionally comprise Supplemental high potency Sweeten or packaged or contained in opaque material. erS Such as Saccharine, aspartame, thaumatin, potassium 8. (canceled) 9. The fortified food composition of claim 1 or 2, wherein acetylsulfame and mixtures thereof. Other suitable high the food composition is a botanical juice. potency Sweeteners that become permitted for use or com 10. The fortified food composition of claim 1 or 2, mercially available from time to time can also be used. wherein the food composition is a chewing gum. 0131 Suitable gum bases are known in the art and the 11. A cereal, comprising: skilled artisan will not have difficulty in selecting suitable base(s) for use herein. (i) at least one cereal ingredient, and 0132) The invention has been described with reference to (ii) about 0.1 ug to 2 mg of isolated adenosylcobalamin. illustrative embodiments and techniques. However, it should 12. A method for treating food cobalamin malabsorption be understood that many variations and modifications may in a host comprising orally administering to the host a be made while remaining within the Spirit and Scope of the fortified food composition comprising a fortifying amount of invention. adenosylcobalamin, mixed with or bound to intrinsic factor, transcobalamin I, transcobalamin II and/or transcobalamin III, wherein the food composition is Selected from the group 1. A fortified food composition comprising a fortifying consisting of a cereal, a gelled confection consisting amount of adenosylcobalamin, mixed with or bound to primarily of Sugars and a fruit base, a chewing confec US 2005/0143340 A1 Jun. 30, 2005

tion, a cereal bar or granola bar, a Supplement, a fruit amount of isolated adenosylcobalamin, mixed with or bound juice, a Vegetable juice, a botanical juice, popcorn, to intrinsic factor, transcobalamin I, transcobalamin II and/ pretzels, nuts, potato chips, and fries. or transcobalamin III, 13. The method of claim 12, wherein the adenosylcobal wherein the food composition is Selected from the group amin is bound to intrinsic factor and/or transcobalamin II. consisting of a cereal, a gelled confection consisting 14. The fortified food composition of claim 1 or 2, primarily of Sugars and a fruit base, a chewing confec wherein the food composition is Selected from the group tion, a cereal bar or granola bar, a Supplement, a fruit consisting of potato chips, pretzels and nuts. juice, a Vegetable juice, a botanical juice, popcorn, 15. The fortified food composition of claim 1 or 2, pretzels, nuts, potato chips, and fries. wherein the food composition is a fruit juice. 27. A method of treating cobalamin deficiency in a host 16. (canceled) who is receiving long term therapy with gastric acid inhibi 17. A method for treating a neurological disorder involv tors or biguanides, comprising administering to the host a ing a cobalamin deficiency in a host, comprising adminis fortified food composition comprising a fortifying amount of tering to the host a fortified food composition comprising a isolated adenosylcobalamin, mixed with or bound to intrin fortifying amount of adenosylcobalamin, mixed with or sic factor, transcobalamin I, transcobalamin II and/or bound to intrinsic factor, transcobalamin I, transcobalamin II transcobalamin III, and/or transcobalamin III, wherein the food composition is wherein the food composition is Selected from the group Selected from the group consisting of a cereal, a gelled consisting of a cereal, a gelled confection consisting confection consisting primarily of Sugars and a fruit base, a primarily of Sugars and a fruit base, a chewing confec chewing confection, a cereal bar or granola bar, a Supple tion, a cereal bar or granola bar, a Supplement, a fruit ment, a fruit juice, a vegetable juice, a botanical juice, juice, a Vegetable juice, a botanical juice, popcorn, popcorn, pretzels, nuts, potato chips, and fries. pretzels, nuts, potato chips, and fries. 18. The method of claim 17, wherein the adenosylcobal 28. (canceled) amin is bound to intrinsic factor and/or transcobalamin II. 29. (canceled) 19. A method for treating pernicious anemia or ataxia in 30. A method for treating neurological disorders in a host, a host comprising administering to the host a fortified food comprising orally administering to the host 0.1 ug to 10 mg composition comprising a fortifying amount of isolated of isolated adenosylcobalamin, optionally mixed with or adenosylcobalamin, mixed with or bound to intrinsic factor, bound to intrinsic factor, transcobalamin I, transcobalamin II transcobalamin I, transcobalamin II and/or transcobalamin and/or transcobalamin III on a daily basis. III, 31. The method of claim 30, wherein the adenosylcobal amin is bound to intrinsic factor and/or transcobalamin II. wherein the food composition is Selected from the group 32. The method of claim 30 or 31, wherein the neuro consisting of a cereal, a gelled confection consisting logical disorder is Alzheimer's disease. primarily of Sugars and a fruit base, a chewing confec 33. The method of claim 30 or 31, wherein the neuro tion, a cereal bar or granola bar, a Supplement, a fruit logical disorder is amyotrophic lateral Sclerosis. juice, a Vegetable juice, a botanical juice, popcorn, 34. The method of claim 30 or 31, wherein the neuro pretzels, nuts, potato chips, and fries. logical disorder is multiple Sclerosis. 20. The method of claim 19, wherein the adenosylcobal 35. A multivitamin formulation comprising adenosylco amin is bound to intrinsic factor and/or transcobalamin II. balamin, mixed with or bound to intrinsic factor, transco 21. A method of treating cobalamin deficiency in a host balamin I, transcobalamin II and/or transcobalamin III, who has atrophic body gastritis, comprising administering to wherein the formulation includes at least one other ingredi the host a fortified food composition comprising a fortifying ent Selected from the group consisting of a vitamin, mineral, amount of isolated adenosylcobalamin, mixed with or bound protein, amino acid, carbohydrate, fat, fatty acid, electrolyte, to intrinsic factor, transcobalamin I, transcobalamin II and/ herb or herbal extract. or transcobalamin III, 36. The formulation of claim 35, wherein the adenosyl cobalamin is bound to intrinsic factor and/or transcobalamin wherein the food composition is Selected from the group II. consisting of a cereal, a gelled confection consisting 37. A method for increasing adenosylcobalamin levels in primarily of Sugars and a fruit base, a chewing confec a host comprising administering to the host a fortified food tion, a cereal bar or granola bar, a Supplement, a fruit composition comprising a fortifying amount of isolated juice, a Vegetable juice, a botanical juice, popcorn, adenosylcobalamin, optionally mixed with or bound to pretzels, nuts, potato chips. and fries. intrinsic factor, transcobalamin I, transcobalamin II and/or 22. The method of claim 21, wherein the adenosylcobal transcobalamin III, amin is bound to intrinsic factor and/or transcobalamin II. wherein the food composition is Selected from the group 23. The food composition of claim 1 or 2, wherein the consisting of a cereal, a gelled confection consisting adenosylcobalamin is at least 50% pure. primarily of Sugars and a fruit base, a chewing confec 24. The food composition of claim 1 or 2, wherein the tion, a cereal bar or granola bar, a Supplement, a fruit adenosylcobalamin is at least 80% pure. juice, a Vegetable juice, a botanical juice, popcorn, 25. The food composition of claim 1 or 2, wherein the pretzels, nuts, potato chips, and fries. adenosylcobalamin is a Single optical isomer. 38. The method of claim 37, wherein the adenosylcobal 26. A method of treating cobalamin deficiency in a host amin is bound to intrinsic factor and transcobalamin II. who has an autoimmune disorder, comprising administering 39. The composition of claim 1, wherein the food com to the host a food composition comprising a fortifying position is a non-citrus or citrus fruit juice. US 2005/0143340 A1 Jun. 30, 2005

40. The composition of claim 39, wherein the juice is a 42. The food composition of claim 1, wherein the food non-citrus juice Selected from the group consisting of apple composition is a cereal. juice, grape juice, pear juice, nectarine juice, currant juice, 43. The food composition of claim 1, wherein the food raspberry juice, gooseberry juice, blackberry juice, blue composition is a gelled confection consisting primarily of berry juice, Strawberry juice, custard-apple juice, pomegran Sugars and a fruit base. ate juice, guava juice, kiwi juice, mango juice, papaya juice, 44. The food composition of claim 1, wherein the food watermelon juice, cantaloupe juice, cherry juice, cranberry composition is a granola bar. juice, pineapple juice, peach juice, apricot juice, plum juice 45. The food composition of claim 1, wherein the food and mixtures thereof. composition is a Supplement. 41. The composition of claim 39, wherein the juice is a 46. The food composition of claim 1, wherein the food citrus juice Selected from the group consisting of orange composition is a vegetable juice. juice, lemon juice, lime juice, grapefruit juice, tangerine juice and mixtures thereof. k k k k k