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(12) Patent Application Publication (10) Pub. No.: US 2005/0143340 A1 Collins (43) Pub 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.
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