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US 2013 0131007A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0131007 A1 BrOWn (43) Pub. Date: May 23, 2013

(54) VITAMIN B12 COMPOSITIONS Publication Classification (71) Applicant: Bebaas, Inc., Carlsbad, CA (US) (51) Int. Cl. A613 L/714 (2006.01) (72) Inventor: Chad Brown, Newport Beach, CA (US) (52) U.S. Cl. CPC ...... A6 IK3I/714 (2013.01) (73) Assignee: BEBAAS, INC., Carlsbad, CA (US) USPC ...... 514/48 (57) ABSTRACT (21) Appl. No.: 13/725,745 This disclosure provides compositions of vitamin B, and methods of treatment or amelioration of a disease associated (22) Filed: Dec. 21, 2012 with vitamin B deficiency. The composition can take the form of a , semi-solid, gummy, or chewable lozenge. The O O composition can also take the form of a troche, a candy, a Related U.S. Application Data wafer, an orally disintegrating , a Sublingual tablet, a (63) Continuation-in-part of application No. 1 1/219,794, buccal tablet, a buccal patch, an oral dissolvable film, an filed on Sep. 7, 2005. aerosol or spray, a , and . US 2013/013 1007 A1 May 23, 2013

VITAMIN B12 COMPOSITIONS SUMMARY OF THE INVENTION

CROSS REFERENCE TO RELATED 0008. Many patients require vitamin B supplementation to combat vitamin B deficiency associated with anemia, APPLICATION pernicious anemia, immune system disorders, nerve damage, 0001. This application is a continuation-in-part of copend partial removal of the stomach or Small intestine, or admin ing U.S. application Ser. No. 1 1/219,794 filed on Sep. 7, istration of drugs known to impair vitamin B. absorption. 2005, herein incorporated by reference in its entirety. Because of the large size of vitamin B, the body neither efficiently metabolizes nor absorbs the vitamin. Existing vita FIELD OF INVENTION min B compositions fail to provide convenient self-admin 0002 The present invention provides improved vitamin istration for patients in a readily absorbable form. These B compositions containing a mixture of vitamin Bana patients often rely on professionally administered vitamin logues in effective amounts for enhanced delivery via the B injections, which are invasive, painful, expensive, and mucosal membranes, such as the mouth, nose, etc., to ame inconvenient. Accordingly, provided herein are composi liorate any condition associated with Vitamin B deficiency tions, methods, and kits that offer superior absorbability and in a human. administration compared to currently available vitamin B treatmentS. 0009 Disclosed herein, in certain embodiments, are com BACKGROUND OF THE INVENTION positions, comprising: (a) cyanocobalamin, hydroxocobal 0003 Vitamin B, otherwise known as cobalamin, is the amin, methylcobalamin in Substantially equivalent ratios; and largest and most structurally complex of the eight water (b) a carrier suitable for forming a solid or semi-solid carrier soluble B vitamins. Vitamin B is a class of cobalt and corrin matrix. In some embodiments, the carrier is a Sugar, Sugar ring molecules that possess vitamin activity. The sixth coor alcohol, (PEG), starch, gum, polymer, or dination site of the corrin ring is either a cyano group (-CN), combination thereof. In some embodiments, the carrier com a hydroxyl group (-OH), a methyl group (-CH-) or a prises isomalt, a PEG, or a combination thereof. In some 5'-deoxyadenosyl group, creating four forms of vitamin B2, embodiments, the PEG is PEG-8000. In some embodiments, including, cyanocobalamin, hydroxocobalamin, methylco the carrier comprises PEG-8000, and isomalt, or a derivative balamin, and adenosylcobalamin. thereof. In some embodiments, the compositions further 0004 Vitamin B is synthesized by microbes, but not by comprise a lubricant. In some embodiments, the lubricant is humans or plants. Gastrointestinal absorption of vitamin B. magnesium stearate. In some embodiments, the compositions from food or Supplements, depends on the presence of Suffi further comprise a flavoring agent. In some embodiments, the cient intrinsic factor and calcium ions. Adenosylcobalamin flavoring agent is: apple, almond, amaretto, anise, apricot, and methylcobalamin are the active forms of vitamin B in banana, banana orange, blackberry, black cherry, black cur humans. Vitamin B2 deficiency may result from intrinsic rant, black walnut, blueberry, brandy, bubblegum, butter rum, factor deficiency (pernicious anemia), partial or total gastrec butterscotch, caramel, cinnamon, citrus, citrus punch, cherry, tomy, or diseases of the distal ileum, intestinal problems and chocolate, chocolate banana pie, chocolate covered cherry, nerve damage, etc. Conditions that make people Vulnerable to chocolate hazelnut, cloves, coconut, coffee, cotton candy, Vitamin B2 deficiency include: Crohn's disease, multiple creme de menthe, egg nog, English toffee, ginger, grape, sclerosis, HIV/AIDS, advanced age (>65 years), chronic grapeade, grape bubblegum, grapefruit, fig, hazelnut, honey, intestinal inflammation, intestinal Surgery, food moving too Irish , kiwi, lavender, lemon, licorice, lime, maple, quickly through the intestine, strict vegetarian diets, exces marshmallow, mint, mocha, molasses, orange, orange cream, sive alcohol consumption for longer than 2 weeks, long-term passion fruit, peach, pecan, peppermint, pina colada, pine use of acid reducing drugs, or drug-therapy associated with apple, pistachio, plum, praline, pomegranate, pumpkin, rasp anemia. berry, redlicorice, root beer, Sassafras, sour apple, spearmint, 0005 Vitamin B has also been used in the treatment of Strawberry, strawberry cream, tangerine, tropical fruit, tutti IgE-mediated allergic diseases, such as allergic rhinitis and fruiti, Vanilla, walnut, watermelon, white chocolate, wild asthma. Oral ingested vitamin B is ineffective in the treat cherry, or wintergreen. In some embodiments, the flavoring ment of allergic disease, possibly due to liver metabolism. agent is cherry. In some embodiments, the composition is 0006 Cyanocobalamin (Crystamine, Cyomin, Crysti formulated as a lozenge, a candy, a wafer, a tablet, a patch, a 1000, Nascobal(R) is the most widely sold analogue of vita film, a spray, a lip balm, or gum. In some embodiments, the min B. Cyanocobalamin is available in injectable (Subcu composition is formulated as a lozenge. In some embodi taneous or intramuscular) and oral forms and has the advan ments, the cyanocobalamin, hydroxocobalamin, and methyl tage of having a stable shelf life at Standard temperature and cobalamin, together, comprise about 1.2% wt/wt of the com pressure (STP). Nascobal(R), an intranasal gel formulation of position. In some embodiments, the compositions comprise cyanocobalamin, has been clinically shown to maintain Substantially equivalent ratios of cyanocobalamin, hydroxo adequate serum levels of vitamin B. The nasal gel can be cobalamin, and methylcobalamin, as well as isomalt, poly self-administered through a nasal delivery system that avoids ethylene glycol, flavoring, and magnesium Stearate. the discomfort of intramuscular injections of B. 0010 Disclosed herein, in certain embodiments, is a 0007 Since vitamin B is very large, orally ingested method for treating or ameliorating vitamin B deficiency in cyanocobalamin is improperly digested and only small a human in need thereof, comprising: administering to the amounts of the vitamin get absorbed by the host. The draw human a composition comprising (a) methylcobalamin, back of the injectable form is that it is invasive, expensive, and hydroxocobalamin, and cyanocobalamin in Substantially inconvenient. Hence, there is a need for more effective forms equivalent ratios, (b) a carrier Suitable for forming solid or of vitamin B that can be absorbed more easily to ameliorate semi-solid carrier matrix, (c) a flavoring agent, and option conditions associated with vitamin B deficiency. ally, (d) a lubricant. In some embodiments, the composition US 2013/013 1007 A1 May 23, 2013

comprises: (a) methylcobalamin, hydroxocobalamin, and 0016. Also described herein in certain embodiments, is a cyanocobalamin in Substantially equivalent ratios, (b) iso method for treating or ameliorating a disease associated with malt, (c) PEG, (d) cherry flavoring, and, optionally, (e) mag Vitamin B2 deficiency, comprising: administering the com nesium Stearate. In some embodiments, the composition position described herein. comprises: (a) methylcobalamin, hydroxocobalamin, and 0017. Also described herein in certain embodiments, is a cyanocobalamin in Substantially equivalent ratios, (b) iso kit, comprising: the composition described herein and malt, (c) PEG, (d) cherry flavoring, and (e) magnesium Stear instructions for use. ate. In some embodiments, the vitamin B2 deficiency is asso ciated with anemia. In some embodiments, the vitamin B Certain Definitions deficiency is associated with pernicious anemia. In some embodiments, the vitamin B deficiency is associated with: 0018. The following terms used in the specification and Graves disease, hypothyroidism, thyroiditis, vitiligo, Addi claims shall have the following meanings for the purpose of son's disease, atrophic gastritis, and/or thrombocytopenia. In the Application. Unless otherwise defined, all technical terms Some embodiments, the vitamin B2 deficiency is associated used herein have the same meaning as commonly understood with: amyotrophic lateral sclerosis (ALS), multiple sclerosis by one of ordinary skill in the art to which this invention (MS), Crohn's disease, Celiac disease, ulcerative colitis, belongs. Alzheimer's disease, HIV/AIDS, joint inflammation, and/or 0019. As used in this specification and the appended arthritis. In some embodiments, the vitamin B deficiency is claims, the singular forms “a,” “an,” and “the include plural associated with the administration of drugs known to impair references unless the context clearly dictates otherwise. Any absorption of vitamin B. In some embodiments, the drug reference to “or herein is intended to encompass “and/or known to impair absorption of vitamin B2 is: a gastric acid unless otherwise stated. inhibitor, a biguanide, a proton pump inhibitor, an H receptor 0020. The term “active ingredients or compounds” of the antagonist, metformin, and/or chloramphenicol. invention refers to cobalamins including, but not limited to, 0011. In some embodiments, the drug known to impair adenosylcobalamin, cyanocobalamin, methylcobalamin, absorption of vitamin B is methotrexate. In some embodi hydroxocobalamin, etc. The active ingredients are used in ments, the vitamin B2 deficiency is associated with ataxia. In different mixtures containing varying effective amounts of Some embodiments, the vitamin B2 deficiency is associated each active compound of the invention, which would be suit with partial removal of the stomach or small intestine. In able for the treatment of different types of vitamin B defi some embodiments, the vitamin B deficiency is associated ciencies. with alcoholism. In some embodiments, the hereditary disor 0021. The term “mixture” refers to a combination contain der is selected from: Alagille's syndrome, severe methylene ing different types of active ingredients defined above, in tetrahydrofolate reductase deficiency, homocystinuria, and/ effective amounts, useful for the treatment of vitamin B or transcobalamin deficiency. deficiency. 0022. The term “effective amount” refers to that amount, 0012 Disclosed herein, in certain embodiments, is a kit, which when administered, either alone or in a mixture, is comprising: a composition comprising (a) methylcobalamin, sufficient to effect the treatment of a condition with vitamin hydroxocobalamin, and cyanocobalamin in Substantially B deficiency. equivalent ratios, (b) a carrier Suitable for forming solid or semi-solid carrier matrix, (c) a flavoring agent, and option 0023 The term “inert ingredients’ refers to components ally, (d) a lubricant. In some embodiments, the composition like pharmaceutically acceptable carriers, adjuvant, diluents comprises: (a) methylcobalamin, hydroxocobalamin, and or , etc., that must be compatible with the other cyanocobalamin in Substantially equivalent ratios, (b) iso ingredients of the formulation and not deleterious to the malt, (c) PEG, (d) cherry flavoring, and, optionally, (e) mag recipient thereof. nesium Stearate. In some embodiments, the composition 0024. The term “composition' or a “formulation” as used comprises: (a) methylcobalamin, hydroxocobalamin, and herein refers to a product comprising the specified active cyanocobalamin in Substantially equivalent ratios, (b) iso ingredients in the specified amounts, as well as any product malt, (c) PEG, (d) cherry flavoring, and (e) magnesium Stear which results, directly or indirectly, from the combination of ate. In some embodiments, the kit further comprises instruc the specified active ingredients in the specified amounts. Such tions for use. term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or DETAILED DESCRIPTION OF THE INVENTION indirectly, from combination, complexation, or aggregation 0013 Existing vitamin B compositions fail to provide of any two or more of the ingredients, or from dissociation of users with a composition that provides an adequate absorp one or more of the ingredients, or from other types of reac tions or interactions of one or more of the ingredients. tion profile in a conveniently self-administered medium. Accordingly, the pharmaceutical compositions of the present 0014 Advantages of the compositions, methods, and kits invention encompass any composition made by mixing any described herein include, but are not limited to, providing a active compound of the present invention and a pharmaceu non-invasive medium for vitamin B self-administration. tically acceptable carrier. Additional advantages of the compositions, methods, and kits 0025. The phrase “substantially equivalent ratio” means described herein include, providing a lower cost alternative to the ratio of one component to another component (for traditional vitamin Badministration. example, the ratio of methylcobalamine to hydroxycobal 0.015 Described herein, in certain embodiments is a com amin to cyanocobalamin) is the same, plus or minus about position, comprising: cyanocobalamin, hydroxocobalamin 30%, about 25%, about 20%, about 15%, about 10%, about and methylcobalamin in Substantially equivalent ratios. 5%, about 2.5%, about 1%. US 2013/013 1007 A1 May 23, 2013

0026. The terms “administration of and/or “administer 0035 Examples of suitable polysaccharides, including, ing a composition refers to providing any composition of the but are not limited to: hydroxypropyl methylcellulose, invention, in any formulation, to a human in need of treat hydroxypropyl cellulose, hydroxypropyl cellulose ethers, ment. hydroxyethyl cellulose, sodium carboxymethyl cellulose, 0027. The term “buccal” refers to delivery of a drug by croScarmellose Sodium, , ethyl cellulose, passage of the drug through the buccal mucosa into the blood microcrystalline cellulose, low-substituted hydroxypropyl Stream. cellulose, pullulan, dextran, dextrin, levan, elsinan, chitosan, 0028. As used herein, “buccal mucosa” refers to the epi pectins, starches, cellulose acetate phthalate, cellulose thelial membranes lining the mouth, including the cheek and acetate butyrate, amylase starch, hydroxypropylated high under the tongue (Sublingual). amylase starch, sodium alginate, alginic acid, carboxymethyl cellulose, derivatives thereof, or any combinations thereof. Compositions 0036) Examples of suitable proteins include, but are not 0029 Disclosed herein, in certain embodiments, are com limited to, collagen, Zein, soy protein isolate, whey protein positions, comprising: cyanocobalamin, hydroxocobalamin, isolate, gluten, casein, gelatin, derivatives thereof, or any and methylcobalamin in Substantially equivalent ratios. In combinations thereof. Some embodiments, the composition further comprises a car 0037 Examples of suitable , include, but are not rier suitable for forming solid or semi-solid carrier matrix. In limited to: , , candelilla , carnuba wax, other embodiments, the composition also comprises a lubri rice wax, ouricurry wax, esparto grass wax, cork fibre wax, cant. In some embodiments, the composition further com Sugarcane wax, microcrystalline waxes, paraffins and oZok prises a flavoring agent. erite, polyethylene waxes, olefin wax, -modified ole 0030. In some embodiments, the composition comprises a fin wax, derivatives thereof, or any combinations thereof. carrier suitable for forming solid or semi-solid carrier matrix. 0038 Examples of suitable gums, include, but are not In some embodiments, the carrier is selected from water, limited to: Xanthan gum, tragacanth gum, acacia gum, arabic Sugar or Sugar Substitutes, Sugar alcohol, polyethylene glycol, gum, gellan gum, carrageenan, locust bean gum, guar gum, alcohols, glycerin, or phospholipids, proteins, waxes, derivatives thereof, or any combinations thereof. gums, or polymers. 0039 Examples of suitable polymers, include, but are not 0031 Examples of suitable sugars include, but are not limited to: vinyl polymers and copolymers, acrylic acid poly limited to, granulated Sugar, powdered Sugar, isomalitulose, mers and copolymers, polyethylene oxides, polyacrylates, lactosucrose, corn , corn Syrup , high fructose corn polyvinylpyrrolidone, polyvinyl alcohol, HPMC K15, 5-me syrup, honey, maple syrup, maltodextrin, crystalline-fruc thyl-pyrrolidinone chitosan, derivatives thereof, or any com tose, dextrose, nonpareils, Stevia Sugar, acesulfame K, aspar binations thereof. tame, neotame, saccharin, Sucralose, trehalose, tagatose, 0040 Exemplary additional carriers that may be used with fructo-oligosaccaride, derivatives thereof, or any combina the compositions disclosed herein include, but are not limited tions thereof. to, glycerin, silicone, jelly, petrolatum, parabens, 0032 Examples of suitable sugar alcohols include, but are derivatives thereof, or any combinations thereof. not limited to, , xylitol, maltitol, isomalt, , 0041. In some embodiments, the carrier comprises an iso , erythritol, hydrogenated Starch hydrosates, deriva malt and PEG-8000. tives thereof, or any combinations thereof. In some embodi 0042. In some embodiments, the lubricant is selected ments, the carrier comprises isomalt or a derivative thereof. from: magnesium Stearate, calcium Stearate, Stearic acid, Exemplary isomalt derivatives include, but are not limited to, Sodium Stearylfumarate, talc, hydrogenated vegetable oils galenIQTM 720, galenIQTM 721, galen IQTM 800/810, gale and polyethylene glycol. In some embodiments, the lubricant nIQTM 960/980, galen IQTM 981, and galenIQTM 990. is magnesium Stearate. 0033 Examples of suitable polyethylene glycols (PEGs) 0043. In some embodiments, the flavoring agent is include, but are not limited to, PEGs with molecular weights selected from: synthetic oils and flavoring aromatics between 900 and 8500, including PEG-1000, -1450, -1500, and/or oils, oleoresins and extracts derived from plants, -2000, -3000,-4000, -5000, -6000, -7000, -8000, derivatives leaves, flowers, fruits, and so forth, and combinations thereof. thereof, or any combinations thereof. In some embodiments, Non-limiting representative flavor oils include spearmint , the carrier comprises PEG-8000. cinnamon oil, oil of wintergreen (methyl salicylate), pepper 0034 Examples of suitable oils and phospholipids mint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, include, but are not limited to, , essential oil, castor cedar leaf oil, oil of nutmeg, allspice, oil of Sage, mace, oil of oil, fatty acids, vegetable oils, Sweet almond oil, apricot ker bitter almonds, and cassia oil. Also useful flavorings are arti nel oil, avocado oil, grapeseed oil, hemp seed oil, macadamia ficial, natural and synthetic fruit such as Vanilla, and oil, olive oil, and Sunflower oil, coconut oil, palm oil, mango citrus oils including lemon, orange, lime, grapefruit, and fruit butter, and shea butter, purified egg or soya lecithins (lecithin essences including apple, pear, peach, grape, Strawberry, E100, lecithin E80 and phospholipons, for example, phos raspberry, cherry, plum, pineapple, apricot and so forth. pholipon 90), ceramides, hydrogenated phospholipids, phos These flavoring agents may be used in or Solid form and phatidylethanolamine, phosphatidylglycerol, phosphotidyl may be used individually or in admixture. Commonly used choline, phosphatidylserine, flavors include mints such as peppermint, menthol, artificial dipalmitoylphosphatidylcholine, dipalmitoylglycerophos Vanilla, cinnamon derivatives, and various fruit flavors, phatidylcholine, dimyristoylphosphatidylcholine, dis whether employed individually or in admixture. Other useful tearoylphosphatidylcholine, cardiolipin, phosphatidylinosi flavorings include aldehydes and esters such as cinnamyl tol, glycerophosphocholine, phosphatidic acid, acetate, cinnamaldehyde, citral diethylacetal, dihydrocarvyl sphingomyelin, derivatives thereof, or any combinations acetate, eugenyl formate, p-methylamisol, and so forth may thereof. be used. Generally any flavoring or such as US 2013/013 1007 A1 May 23, 2013

those described in Chemicals Used in Food Processing, pub 0048. In some embodiments, a composition disclosed lication 1274, pages 63-258, by the National Academy of herein comprises, by way of non-limiting examples, 50-99. Sciences, may be used. 5%, 55-99.5%, 60-99.5%, 65-99.5%, 70-99.5%, 75-99.5%, 0044) Further examples of aldehyde flavorings include but 80-99.5%, 85-99.5%, 90-99.5%, 91-99.5%, 92-99.5%, are not limited to acetaldehyde (apple), benzaldehyde 93-99.5%, 94-99.5%, 95-99.5%, 96-99.5%, 97-99.5%, (cherry, almond), anisic aldehyde (licorice, anise), cinnamic 98-99.5%, or 99-99.5% weight/weight carrier. aldehyde (cinnamon), citral, i.e., alpha-citral (lemon, lime), 0049 Disclosed herein, in certain embodiments, are com neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), positions, comprising: (a) methylcobalamin, hydroxocobal ethyl Vanillin (vanilla, cream), heliotrope, i.e., piperonal (va amin, and cyanocobalamin in Substantially equivalent ratios, nilla, cream), Vanillin (vanilla, cream), alpha-amyl cinnama (b) a carrier suitable for forming solid or semi-solid carrier ldehyde (spicy fruity flavors), butyraldehyde (butter, cheese), matrix, (c) a flavoring agent, and optionally, (d) a lubricant. Valeraldehyde (butter, cheese), citronellal (modifies, many Further disclosed herein are compositions, comprising: (a) types), decanal (citrus fruits), aldehyde C-8 (citrus fruits), methylcobalamin, hydroxocobalamin, and cyanocobalamin aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), in substantially equivalent ratios, (b) isomalt, (c) PEG, (d) 2-ethyl butyraldehyde (berry fruits), hexenal, i.e., trans-2 cherry flavoring, and, optionally, (e) magnesium Stearate. (berry fruits), tolyl aldehyde (cherry, almond), Veratralde Additionally disclosed herein are compositions, comprising: hyde (vanilla), 2,6-dimethyl-5-heptenal, i.e., melonal (a) methylcobalamin, hydroxocobalamin, and cyanocobal (melon), 2,6-dimethyloctanal (green fruit), and 2-dodecenal amin in Substantially equivalent ratios, (b) isomalt, (c) PEG, (citrus, mandarin), cherry, grape, Strawberry shortcake, mix (d) cherry flavoring, and (e) magnesium Stearate. tures thereof and the like. 0050. The skilled artisan will appreciate that the combi 0045. In some embodiments, the compositions further nation of active ingredients found in the compositions comprise antimicrobial agents, plasticizing agents, Sulfur described above also may be administered separately. In addi precipitating agents, saliva stimulating agents, cooling tion, the administration of one element may be prior to, con agents, Surfactants, stabilizing agents, emulsifying agents, current to, or Subsequent to the administration of other ele thickening agents, binding agents, coloring agents, Sweeten ment(s). ers, fragrances, and the like. Exemplarily Sulfur precipitating 0051. Further, compositions of the present invention may agents useful in the present invention include metal salts such be used in combination with other drugs that are used in the as copper salts (e.g., copper gluconate) and Zinc salts (e.g., treatment/prevention/suppression or amelioration of vitamin Zinc citrate and Zinc gluconate). Exemplarily saliva stimulat B deficiencies or conditions. Such other drugs may be ing agents include, but are not limited to food acids such as administered, by a route and in an amount commonly used citric, lactic, malic. Succinic, ascorbic, adipic, fumaric and therefore, contemporaneously or sequentially with a compo tartaric acids. sition of the present invention. When a composition of the 0046. The weight ratio of the respective ingredients may present invention is used contemporaneously with one or be varied when necessary and will depend upon the effective more other drugs or herbal Supplements, vitamin Supple dose of each ingredient or the effective dose of the combina ments, etc., a pharmaceutical composition containing Such tion of all the active ingredients in a formulation. Generally, other drugs in addition to the composition of the present an effective dose of each will be used. In a particularly pre invention is preferred. Accordingly, the pharmaceutical com ferred embodiment, a combination of active ingredients is positions of the present invention include those that also used in the composition, for example, methylcobalamin, contain one or more other active ingredients, in addition to the hydroxocobalamin, and cyanocobalamin. In a preferred compositions of the present invention. embodiment, a combination of active ingredients is used in the composition, for example, adenosylcobalamin: hydroxo Formulations cobalamin: cyanocobalamin. Generally, the active ingredi 0.052 Disclosed herein in certain embodiments, are com ents occur as Substantially equivalent ratios. In some embodi positions, comprising: methylcobalamin, hydroxocobal ments, the composition comprises Substantially equivalent amin, and cyanocobalamin in Substantially equivalent ratios. ratios of methylcobalamin, hydroxocobalamin, and cyanoco In some embodiments, the composition further comprises a balamin. Alternatively, in Some embodiments, the composi carrier suitable for forming solid or semi-solid carrier matrix. tion comprises Substantially equivalent ratios of adenosylco In other embodiments, the composition also comprises a balamin, cyanocobalamin, and hydroxocobalamin. The lubricant. In some embodiments, the composition further amount of adenosylcobalamin and hydroxocobalaminadvan comprises a flavoring agent. In some embodiments, the com tageously will generally range from 250-750 ug, while the positions are formulated for . range for cyanocobalamin will generally range from 1500 0053 Disclosed herein, in certain embodiments, are com 2500 g in a 3 mg cobalamin formulation. Other combina positions, comprising: (a) methylcobalamin, hydroxocobal tions of active ingredients of the present invention are also amin, and cyanocobalamin in Substantially equivalent ratios, possible as is understood in the art. (b) a carrier suitable for forming solid or semi-solid carrier 0047. In some embodiments, a composition disclosed matrix, (c) a flavoring agent, and optionally, (d) a lubricant; herein comprises, by way of non-limiting example, 0.5%-2. wherein the composition is formulated for oral and/or trans 0%, 0.6%-2.0%, 0.7%-2.0%, 0.8%-2.0%, 0.9%-2.0%, 1.0-2. mucosal administration. Further disclosed herein are compo 0%, 1.1%-2.0%, 1.2%-2.0%, 1.3%-2.0%, 1.4%-2.0%, 1.5%- sitions, comprising: (a) methylcobalamin, hydroxocobal 2.0%, 1.6%-2.0%, 1.7%-2.0%, 1.8%-2.0%, 1.9%-2.0%, amin, and cyanocobalamin in Substantially equivalent ratios, 0.5%-0.6%, 0.5%-0.7%, 0.5%-0.8%, 0.5%-0.9%, (b) isomalt, (c) PEG, (d) cherry flavoring, and, optionally, (e) 0.5%-1.0%, 0.5%, 1.1%, 0.5%-1.2%,0.5%-1.3%, magnesium Stearate; wherein the composition is formulated 0.5%-1.4%, 0.5%-1.5%, 0.5%-1.6%, 0.5%-1.7%, for oral and/or transmucosal administration. Additionally dis 0.5%-1.8%, or 0.5%-1.9%, weight/weight cobalamins. closed herein are compositions, comprising: (a) methylcobal US 2013/013 1007 A1 May 23, 2013

amin, hydroxocobalamin, and cyanocobalamin in Substan discussed above, sufficient to produce the desired effect upon tially equivalent ratios, (b) isomalt, (c) PEG, (d) cherry the process or condition of diseases. flavoring, and (e) magnesium Stearate; wherein the composi tion is formulated for oral and/or transmucosal administra Tablets tion. 0057. In some embodiments, the compositions disclosed 0054. It is the primary object of the present invention to herein are formulated as tablets, e.g., fast dissolving tablets. provide patient-friendly modes of delivery to patients of such 0058. In some embodiments, the tablet is formulated to effective amounts of vitamin B analogues without the dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 inconvenience and discomfort of subcutaneous and intramus second to 20 minutes, 1 second to 15 minutes, 1 second to 14 cular injections. In accordance with the invention, Vitamin minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 B is instilled in a carrier matrix, Such as controlled-release second to 11 minutes, 1 second to 10 minutes, 1 second to 9 lozenges, troches, tablets, hard or soft capsules, or minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 , pressed pills, gel caps, chewing gum, gels such as second to 6 minutes, 1 second to 5 minutes, 1 second to 4 metered gels that can be administered intranasally, nasal minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 drops, creams, , aqueous or oily Suspensions, dispers second to 1 minute, or 1 second to 30 seconds. ible or granules, , sprays or aerosols using 0059 Tablets contain the active ingredient in admixture flowing propellants, like liposomal sprays, nasal sprays, etc., with non-toxic pharmaceutically acceptable excipients which and , transdermal patches, etc., all for are suitable for the manufacture of tablets. These excipients patient-friendly, self-administration of effective amounts of may be for example, inert diluents, such as calcium carbon Vitamin B. The invention thereby minimizes inconvenience ate, Sodium carbonate, lactose, calcium phosphate or Sodium and discomfort for the patient and alleviates the burden and phosphate; granulating and disintegrating agents, for time demands imposed on medical staff. In some embodi example, corn starch, or alginic acid; ments, the compositions disclosed herein are formulated for 0060 binding agents, for example starch, gelatin or aca transdermal administration. In some embodiments, the com cia, and lubricating agents, for example magnesium Stearate, positions are formulated as lozenges, candies, tablets, wafers, Stearic acid or talc. The tablets may be uncoated or they may films, sprays, gums, lip balms, or patches. The vitamin B in be coated by known techniques to delay disintegration and formulations such as lozenges, troches, tablets, hard or soft absorption in the and thereby provide a capsules, gums, film, wafers, sprays, patches and lip balms, Sustained action over a longer period. For example, a time etc., are preferably absorbed directly via the mucosa, such as delay material such as glyceryl monostearate or glyceryl dis buccal, nasal mucosa, into the blood stream before being tearate may be employed. They may also be coated by the subjected to digestion and degradation in the liver. Preferred techniques described in the U.S. Pat. Nos. 4.256,108; 4,166, Vitamin B formulations include nasal gels, lozenges, 452; and 4.265,874 to form osmotic therapeutic tablets for including Sublingual lozenges, nasal drops, nasal or pulmo control release. nary or other mucosal sprays, including liposomal sprays, fast absorbing capsules or tablets, gums, films, wafers, patches Capsules and lip balms. 0055 Thus, the vitamin B formulations of the present 0061. In some embodiments, the compositions disclosed invention may be administered, but are not limited to, oral, herein are formulated as capsules, e.g., hard capsules or soft parenteral (e.g., intramuscular, intraperitoneal, intravenous, capsules. ICV, intracisternal or infusion, Subcutaneous injec 0062. In some embodiments, the is formulated to tion, or implant), by inhalation spray, intranasal, transbuccal, dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 mucosal, pulmonary, transdermal, liposomal, vaginal, rectal, second to 20 minutes, 1 second to 15 minutes, 1 second to 14 Sublingual, or topical routes of administration and may be minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 formulated, alone or together, in Suitable dosage unit formu second to 11 minutes, 1 second to 10 minutes, 1 second to 9 lations containing conventional non-toxic pharmaceutically minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 acceptable carriers, adjuvants and vehicles appropriate for second to 6 minutes, 1 second to 5 minutes, 1 second to 4 each . minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 second to 1 minute, or 1 second to 30 seconds. 0056. The pharmaceutical compositions for the adminis 0063. Wherein the composition is formulated as a hard tration of the compositions of this invention may conve capsule, in Some embodiments, the composition is mixed niently be presented in dosage unit form and may be prepared with an inert Solid diluent, for example, calcium carbonate, by methods well known in the art of pharmacy. Suitable calcium phosphate or kaolin. Where the composition is for methods are described in, for example, Remington: The Sci mulated as a Soft capsule, in Some embodiments, the compo ence and Practice of Pharmacy, ed. Gennaro et al., 20th Ed. sition is mixed with water or an oil medium, for example (2000), although the skilled artisan will recognize that other peanut oil, , or olive oil. methods are known and are suitable for preparing the com positions of the present invention. All methods include the LOZenge step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. 0064. In some embodiments, the compositions disclosed In general, the pharmaceutical compositions are prepared by herein are formulated as lozenges. In some embodiments, the uniformly and intimately bringing the active ingredient into lozenges may include hard lozenges, soft lozenges, gummy association with a liquid carrier or a finely divided solid lozenges, or chewable lozenges. carrier or both, and then, if necessary, shaping the product 0065. In some embodiments, the lozenge is formulated to into the desired formulation. In the pharmaceutical composi dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 tion the active ingredient is included in an effective amount, second to 20 minutes, 1 second to 15 minutes, 1 second to 14 US 2013/013 1007 A1 May 23, 2013

minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 0073. In some embodiments, the elastomer solvent com second to 11 minutes, 1 second to 10 minutes, 1 second to 9 prises methyl, or esters of rosins or minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 modified rosins, such as hydrogenated, dimerized or poly second to 6 minutes, 1 second to 5 minutes, 1 second to 4 merized rosins, or mixtures thereof. Examples of elastomer minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 solvents suitable for use herein include the pentaerythritol second to 1 minute, or 1 second to 30 seconds. ester of partially hydrogenated wood rosin and partially hydrogenated wood rosin, pentaerythritol ester of wood Candy rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol 0066. In some embodiments, the compositions disclosed ester of tall oil rosin, glycerolester of wood rosin and partially herein are formulated as candies. In some embodiments, the hydrogenated wood rosin and the partially hydrogenated candy may include hard candy, Soft candy, gummy candy, or methyl ester of rosin, such as polymers of alpha-pinene or chewy candy. beta-pinene, terpene resins including polyterpene and mix 0067. In some embodiments, the candy is formulated to tures thereof. dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 0074. A variety of traditional ingredients such as plasti second to 20 minutes, 1 second to 15 minutes, 1 second to 14 cizers or softenerS Such as lanolin, Stearic acid, Sodium Stear minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 ate, potassium Stearate, glyceryl triacetate, glycerine and the second to 11 minutes, 1 second to 10 minutes, 1 second to 9 like, for example, natural waxes, petroleum waxes such as minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 polyurethene waxes, paraffin waxes and microcrystalline second to 6 minutes, 1 second to 5 minutes, 1 second to 4 waxes may also be incorporated into the gum formulations minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 disclosed herein to obtain a variety of desirable textures and second to 1 minute, or 1 second to 30 seconds. consistency properties. Film Lip Balm 0068. In some embodiments, the compositions disclosed herein are formulated as films, e.g., dissolvable films. The 0075. In some embodiments, the compositions disclosed film, by way of non-limiting example, is a clear or opaque, herein are formulated as lip balms. In some embodiments, the flexible, thin material. lip balm may be in a tube, Stick, or pot. 0069. The film-forming carrier used in the film formula 0076. In some embodiments, the lip balm formulations tions is selected from the group consisting of pullulan, further comprise a wax or other pharmaceutically acceptable hydroxypropylmethyl cellulose, hydroxyethyl cellulose, vehicle, emollients, and oils. hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxym 0077 Suitable waxes include animal waxes, plant waxes, ethyl cellulose, polyvinyl alcohol, Sodium alginate, polyeth mineral waxes, silicone waxes synthetic waxes and petroleum ylene glycol, Xanthan gum, tragacanth gum, guar gum, acacia waxes. Exemplary specific waxes include, but are not limited gum, arabic gum, polyacrylic acid, methylmethacrylate to, , ; white wax, : copolymer, carboxyvinyl polymer, amylose, high amylose beeswax, jojoba wax; oZokerite; polyethylene; and combina starch, hydroxypropylated high amylose starch, dextrin, pec tions thereof. tin, chitin, chitosan, levan, elsinan, collagen, gelatin, Zein, 0078. In some embodiments, the lip balm formulations gluten, soy protein isolate, whey protein isolate, casein and further comprise an oil or a butter, e.g., Sunflower oil, coconut mixtures thereof. oil, , , corn oil, aloe Vera oil, canola oil, 0070. In some embodiments, the film is formulated to Soybean oil, jojoba oil, olive oil, babassu oil, avocado oil, dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 apricot oil, meadowfoam seed oil, macademia seed oil, oat second to 20 minutes, 1 second to 15 minutes, 1 second to 14 kernel oil, palm seed oil, safflower oil, sandalwood oil, minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 sesame oil, almond oil, germ oil, cranberry oil, mango second to 11 minutes, 1 second to 10 minutes, 1 second to 9 seed butter, raspberry butter, avocado butter, shea butter, olive minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 butter, kuku butter, monoi butter, peach butter, pistachio but second to 6 minutes, 1 second to 5 minutes, 1 second to 4 ter, coconut butter, cocoa butter, pomegranate butter, rose hip minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 butter, sunflower butter, wheat germ butter, apricot butter, second to 1 minute, or 1 second to 30 seconds. babassu butter, cupuacu butter, kokum butter, hazelnut butter, jojoba butter, sesame butter, soy butter, almond butter, mead Gums owfoam seed butter, black current seed butter and cranberry butter. 0071. In some embodiments, the compositions disclosed herein are formulated as gums. In some embodiments, the Buccal Patch gum may be non degradable chewing gum, degradable chew ing gum, or liquid filled chewing gum. 0079. In some embodiments, the compositions disclosed 0072. In some embodiments, the gum formulations further herein are formulated as buccal patches. In some embodi comprise natural and synthetic elastomers and rubbers. For ments, the buccal patch, by way of non-limiting example, is a example, carriers Suitable for a gum formulation include, but clear or opaque, flexible, thin material. are not limited to, Substances of vegetable origin such as 0080. In some embodiments, the buccal patch is fabricated chicle, jelutong, gutta percha and crown gum. Synthetic elas to dissolve gradually over a predetermined time period. In tomers such as -styrene copolymers, isobutylene Some embodiments, the buccal patch further comprises a isoprene copolymers, polyethylene, polyisobutylene and bioerodible polymeric carrier, and any excipients that may be polyvinyl-acetate and mixtures thereof, are also useful. desired, e.g., penetration enhancers. As used herein, "bio US 2013/013 1007 A1 May 23, 2013

erodible', i.e., the polymer hydrolyzes at a predetermined disks or strips of medication is described in EP 467172 rate upon contact with moisture. (where a reciprocatable piercing mechanism is used to pierce 0081. In some embodiments, the bioerodible polymeric through opposed surfaces of a blister pack); WO91/02558: carrier comprises a polymer having Sufficient tack Such that WO93/09832; WO94/08522; U.S. Pat. Nos. 4,627,432: the patch adheres to the buccal mucosa for the time period 4,811,731; 5,035,237; 5,048,514; 4,446,862; and 3,425,600. necessary to produce the desired drug release profile. Gener Other patents which show puncturing of single medication ally, the polymeric carriers comprise hydrophilic (water capsules include U.S. Pat. Nos. 4.338.931: 3,991,761; 4.249, soluble and water-swellable) polymers that adhere to the wet 526; 4,069,819: 4,995,385; 4,889,114; and 4,884,565; and EP Surface of the buccal mucosa. Examples of polymeric carriers 469814. WO90/07351 describes a hand-held pump device useful herein include acrylic acid polymers and copolymers, with a loose reservoir. Further dry powder dispensers e.g., those known as “carbomers' for example, Carbopol R. are also covered in U.S. Pat. No. 6,089,228 which specifically Other suitable polymers include, but are not limited to, hydro provides an improved apparatus for aerosolizing a powdered lyzed polyvinyl alcohol, polyethylene oxides (e.g., Sentry medicament, hereby incorporated by reference. PolyoxR), polyacrylates (e.g., GantreZR), vinyl polymers and I0086 Dispersible powders and granules are also suitable copolymers, polyvinylpyrrolidone, dextran, guar gum, pec for preparation of an aqueous by the addition of tins, starches, and cellulosic polymers such as hydroxypropyl water provide the active ingredient in admixture with a dis methylcellulose (e.g., Methocel(R), hydroxypropyl cellulose persing or wetting agent, Suspending agent and one or more (e.g., Kluce(R), hydroxypropyl cellulose; ethers, hydroxy . Suitable dispersing or wetting agents and Sus ethyl cellulose, sodium carboxymethyl cellulose, methyl cel pending agents are exemplified by those already mentioned lulose, ethyl cellulose, cellulose acetate phthalate, cellulose above. Additional excipients, for example Sweetening, flavor acetate butyrate, and the like. ing and coloring agents, may also be present. Syrups and 0082 In some embodiments, the patch is formulated to elixirs may be formulated with Sweetening agents, for dissolve in 1 second to 30 minutes, 1 second to 25 minutes, 1 example glycerol, propylene glycol, Sorbitol or Sucrose. Such second to 20 minutes, 1 second to 15 minutes, 1 second to 14 formulations may also contain a demulcent, , minutes, 1 second to 13 minutes, 1 second to 12 minutes, 1 flavoring and coloring agent. second to 11 minutes, 1 second to 10 minutes, 1 second to 9 I0087. The pharmaceutical compositions may sometimes minutes, 1 second to 8 minutes, 1 second to 7 minutes, 1 be in the form of a sterile injectable aqueous or oleagenous second to 6 minutes, 1 second to 5 minutes, 1 second to 4 Suspension. This Suspension may be formulated according to minutes, 1 second to 3 minutes, 1 second to 2 minutes, 1 the known art using those Suitable dispersing or wetting second to 1 minute, or 1 second to 30 seconds. agents and Suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile Sprays injectable or Suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 0083. In some embodiments, the compositions disclosed 1,3-butane diol. Among the acceptable vehicles and solvents herein are formulated as sprays. In some embodiments, the that may be employed are water, Ringer's solution and iso compositions disclosed herein are formulated as liposomal tonic sodium chloride solution. In addition, sterile, fixed oils sprays. A used for the preparation of the liposomal are conventionally employed as a solvent or Suspending spray comprises of two lipid layers. The lipid layer may be a medium. For this purpose any bland fixed oil may be monolayer, or may be multilameliar and include multiple employed including synthetic mono- or diglycerides. In addi layers. In some embodiments, the liposome comprises phos tion, fatty acids such as oleic acid find use in the preparation phatidylcholine, but can include various natural (e.g., tissue of injectables. derived L-oc-phosphatidyl: egg yolk, heart, brain, liver, Soy I0088. The compositions of the present invention may also bean) and/or synthetic (e.g., Saturated and unsaturated 1.2- be administered in the form of suppositories for rectal admin diacyl-SN-glycero-3 15 phosphocholines, 1-acyl-2-acyl-SN istration of the drug. These compositions can be prepared by glycero-3-phosphocholines, 1.2 diheptanoyl-SN-glycero-3- mixing the drug with a suitable non-irritating which phosphocholine) derivatives of the same. Such lipids can be is solid at ordinary temperatures but liquid at the rectal tem used alone, or in combination with a helper lipid. Preferred perature and will therefore melt in the rectum to release the helper lipids are non-ionic or uncharged at physiological pH. drug. Such materials are cocoa butter and polyethylene gly Non-ionic lipids include, but are not limited to, cholesterol cols. and DOPE (1,2-dioleolylglyceryl 20 phosphatidylethanola 0089 For topical use, creams, gels including nasal gels, mine). Phosphatidic acid, which imparts an electric charge, ointments, jellies, or Suspensions, mouth washes may also be added. and gargles, etc., containing the compositions of the present 0084. In some embodiments, the spray is delivered by a invention, are employed. metered dose pump. In other embodiments, the spray is deliv ered by mist spray pumps or Squeeze bottles. Disorders and Conditions Related to Vitamin B. Deficiency 0090 Disclosed herein in certain embodiments, are com Miscellaneous positions, comprising: methylcobalamin, hydroxocobal 0085 Formulations are also useful as dry powders or gran amin, and cyanocobalamin in Substantially equivalent ratios. ules. Dispersible, dry powders are useful for inhalation after In some embodiments, the composition further comprises a aerosolization with a suitable dispersion device. Dry powder carrier suitable for forming a solid or semi-solid carrier dispersion devices for medicaments are described in a num matrix. In other embodiments, the composition also com ber of patent documents. U.S. Pat. No. 3,921,637 describes a prises a lubricant. In some embodiments, the composition manual pump with needles for piercing through a single cap further comprises a flavoring agent. In some embodiments, sule of powdered medicine. The use of multiple receptacle the compositions are formulated for oral administration. US 2013/013 1007 A1 May 23, 2013

0091 Disclosed herein, in certain embodiments, are com Kits positions, comprising: (a) methylcobalamin, hydroxocobal amin, and cyanocobalamin in substantially equivalent ratios, 0094) Disclosed herein in certain embodiments, are kits, (b) a carrier suitable for forming solid or semi-solid carrier comprising a composition comprising: methylcobalamin, matrix, (c) a flavoring agent, and optionally, (d) a lubricant; hydroxocobalamin, and cyanocobalamin in substantially wherein the composition is formulated for oral and/or trans equivalent ratios. In some embodiments, the composition mucosal administration. Further disclosed herein are compo further comprises a carrier suitable for forming solid or semi sitions, comprising: (a) methylcobalamin, hydroxocobal Solid carrier matrix. In other embodiments, the composition amin, and cyanocobalamin in substantially equivalent ratios, also comprises a lubricant. In some embodiments, the com (b) isomalt, (c) PEG, (d) cherry flavoring, and, optionally, (e) position further comprises a flavoring agent. In some embodi magnesium stearate; wherein the composition is formulated ments, the compositions are formulated for oral administra for oral and/or transmucosal administration. Additionally dis t1On. closed herein are compositions, comprising: (a) cyanocobal 0095 Disclosed herein, in certain embodiments, are kits, amin, hydroxocobalamin, and methylcobalamin in substan comprising compositions comprising: (a) methylcobalamin, tially equivalent ratios, (b) isomalt, (c) PEG, (d) cherry hydroxocobalamin, and cyanocobalamin in substantially flavoring, and (e) magnesium stearate; wherein the composi equivalent ratios, (b) a carrier suitable for forming solid or tion is formulated for oral and/or transmucosal administra semi-solid carrier matrix, (c) a flavoring agent, and option t1On. ally, (d) a lubricant; wherein the composition is formulated 0092. The following diseases, disorders and conditions for oral and/or transmucosal administration. Further dis are related to vitamin B deficiency, and therefore may be closed herein are kits, comprising compositions comprising: treated, controlled or in some cases prevented, by treatment (a) methylcobalamin, hydroxocobalamin, and cyanocobal with the composition of this invention: pernicious anemia; amin in substantially equivalent ratios, (b) isomalt, (c) PEG, ataxia; autoimmune disorders; patients receiving long term (d) cherry flavoring, and, optionally, (e) magnesium stearate: therapy with gastric acid inhibitors like biguanides; patients wherein the composition is formulated for oral and/or trans with atrophic body gastritis, or who have had partial or total mucosal administration. Additionally disclosed herein are gastrectomy; anemia associated with drug-therapy (for kits, comprising compositions comprising: (a) methylcobal example, methotrexate, metformin, phenobarbital, pheny amin, hydroxocobalamin, and cyanocobalamin in substan toin, etc.; alcohol or substance abuse; inflammation of joints; tially equivalent ratios, (b) isomalt, (c) PEG, (d) cherry fla arthritis; burns; neurodegenerative disease like Alzheimer's Voring, and (e) magnesium stearate; wherein the composition disease, amyotrophic lateral sclerosis or multiple sclerosis: is formulated for oral and/or transmucosal administration. Senior dementia; allergic diseases such as rhinitis, allergic I0096) In certain embodiments, the kits comprise a compo asthma, etc.; HIV/AIDS where there poor absorption of vita sition disclosed herein and instructions for storage, adminis min B; irritable bowel syndrome or patients who have tration, dosing, and disease state for which the formulation is undergone intestinal surgery; inflammatory bowel disease, useful, etc. In yet another embodiment is an article of manu including Crohn's disease and ulcerative colitis; suppression facture comprising a composition or formulation disclosed of IgE production; and other disorders where vitamin B herein and an apparatus to dispense or administer the formu deficiency is a component. lation to a given patient, such as a container for housing the 0093. In some embodiments, vitamin B deficiency is composition, etc. associated with anemia. In some embodiments, the vitamin B12 deficiency is associated with pernicious anemia. In some 0097. In some embodiments, the kits described herein embodiments, the Vitamin B12 deficiency is associated with a include the composition described herein, and instructions disease, selected from: Graves disease, hypothyroidism, thy for using the kit. In further embodiments, the kits include roiditis, Vitiligo. Addison's disease, atrophic gastritis, or packaging materials including, but not limited to, blister thrombocytopenia. In some embodiments, the vitamin B packs, bottles, tubes, inhalers, pumps, bags, vials, containers, deficiency is associated with an immune disorder, selected bottles, and any packaging material suitable for a selected from: amyotrophic lateral sclerosis, multiple sclerosis, formulation and intended mode of administration and treat Crohn's disease, Celiac disease, ulcerative colitis, Alzhe ment, including labels listing contents and/or instructions for imer's disease, AIDS, joint inflammation, or arthritis. In some use, and package inserts, with instructions for use. In a further embodiments, the vitamin B deficiency is associated with embodiment, a label is on or associated with the container. In administration of a drug known to impair absorption of vita yet a further embodiment, a label is on a container when min B2, wherein the drug known to impair absorption of letters, numbers or other characters forming the label are Vitamin B12 is selected from: gastric acid inhibitors, bigu attached, molded or etched into the container itself a label is anides, proton pump inhibitors. He receptor antagonists, met associated with a container when it is present within a recep formin, or chloramphenicol. In some embodiments, the vita tacle or carrier that also holds the container, e.g., as a package min B12 deficiency is associated with ataxia. In some insert. In other embodiments a label is used to indicate that the embodiments, the vitamin B deficiency is associated with contents are to be used for a specific therapeutic application. partial removal of the stomach or small intestine. In some In yet another embodiment, a label also indicates directions embodiments, the vitamin B deficiency is associated with for use of the contents, such as in the methods described alcoholism. In some embodiments, the vitamin B defi herein. ciency is associated with Alagille's syndrome, severe meth I0098. In certain embodiments, the composition is pre ylenetetrahydrofolate reductase deficiency, homocystinuria, sented in a pack or dispenser device which contains one or or transcobalamin deficiency. more unit dosage forms containing a composition provided US 2013/013 1007 A1 May 23, 2013

herein. In another embodiment, the pack for example con 0106 Blend 2 is divided into unit dosages and each unit tains metal or plastic foil. Such as a blister pack. In a further dosage is compressed into a tablet. embodiment, the pack or dispenser device is accompanied by instructions for administration. In yet a further embodiment, Example 3 the pack or dispenser is also accompanied with a notice asso ciated with the container inform prescribed by a governmen Treating Vitamin B. Deficiency with Vitamin B tal agency regulating the manufacture, use, or sale of phar Described Herein maceuticals, which notice is reflective of approval by the I0107 Ahuman presents with vitamin B deficiency asso agency of the form of the drug for human or veterinary admin ciated with pernicious anemia, including impaired perception istration. In another embodiment, such notice, for example, is of deep touch and deep muscle-tendon reflexes. The patient the labeling approved by the U.S. Food and Drug Adminis self-administers a vitamin Blozenge according to Example tration for prescription drugs, or the approved product insert. 1. The human’s symptoms of vitamin B deficiency are In yet another embodiment, compositions containing a com decreased. pound disclosed herein formulated in a compatible pharma What is claimed is: ceutical carrier are also prepared, placed in an appropriate 1. A composition, comprising: container, and labeled for treatment of an indicated condition. a. cyanocobalamin, hydroxocobalamin, methylcobalamin EXAMPLES in Substantially equivalent ratios; and b. a carrier suitable for forming a solid or semi-solid carrier Example 1 matrix. 2. The composition of claim 1, wherein the carrier is a Composition Sugar, Sugar alcohol, polyethylene glycol, starch, gum, poly mer, or combination thereof. 0099. A lozenge is prepared. The components of the com 3. The composition of claim 2, wherein the sugar alcohol is position, and their respective amounts, by weight, are listed in isomalt or a derivative thereof. Table 1. 4. The composition of claim 2, wherein the PEG is PEG 8OOO. TABLE 1. 5. The composition of claim 2, wherein the carrier com prises PEG-8000, and isomalt or a derivative thereof. Material Milligram per Unit Dose 6. The composition of claim 1, further comprising a lubri Cyanocobalamin, Hydroxocobalamin, Equal amounts of each Cant. Methylcobalamin Isomalt galenIQTM 721 182.7SO 7. The composition of claim 6, wherein the lubricant is Polyethylene Glycol 8000 62.500 magnesium Stearate. Flavoring O.SOO 8. The composition of claim 1, further comprising a flavor Magnesium Searate 1.2SO ing agent. 9. The composition of claim 8, wherein the flavoring agent is cherry. Example 2 10. The composition of claim 1, wherein the composition is formulated as a lozenge, a candy, a wafer, a tablet, a patch, a Manufacture of Vitamin B Composition film, a spray, a lip balm, or gum. 11. The composition of claim 10, wherein the composition 0100. About 5 grams of cyanocobalamin, about 5 grams of is formulated as a lozenge. hydroxycobalamin acetate and about 5 grams of methylco 12. A method for treating or ameliorating vitamin B balamin are passed through a #20 mesh stainless steel screen. deficiency in a human in need thereof, comprising: adminis 0101. About 15 grams of isomalt is passed through a #20 tering to the human the composition of claim 1. mesh screen and combined with the methyl-, cyano- and 13. The method of claim 12, wherein the vitamin B hydroxy-cobalamin mixture. Pre-blend 1 is mixed until a deficiency is associated with anemia, Graves disease, Substantially homogenous mixture is observed. hypothyroidism, thyroiditis, vitiligo. Addison's disease, atro 0102 About 90 grams of isomalt is passed through a #20 phic gastritis, thrombocytopenia, amyotrophic lateral sclero mesh screen and combined with pre-blend 1. Pre-blend 2 is sis, multiple Sclerosis, Crohn's disease, Celiac disease, ulcer mixed until a Substantially homogenous mixture is observed. ative colitis, Alzheimer's disease, AIDS, joint inflammation, 0103. About 360 grams of isomalt is passed through a #20 arthritis, ataxia, partial removal of the stomach or Small intes mesh screen and combined with pre-blend 2. Pre-blend 3 is tine, alcoholism, Alagille's syndrome, severe methylenetet mixed until a Substantially homogenous mixture is observed. rahydrofolate reductase deficiency, homocystinuria, or Pre-blend 3 is transferred into a blender. transcobalamin deficiency, or any combinations thereof. 0104. About 448.75 grams of isomalt, about 312.5 grams 14. The method of claim 13, wherein the vitamin B of PEG-8000 and about 2.5 grams of cherry flavoring are deficiency is associated with pernicious anemia. passed through a #20 mesh screen and transferred into the 15. The method of claim 12 wherein the vitamin B defi blender with pre-blend 3 and blended until substantially ciency is associated with administration of drugs known to homogenous to generate blend 1. impair absorption of vitamin B. 0105. About 6.250 grams of magnesium stearate is passed 16. The method of claim 15, wherein the drug known to through a #20 mesh screen and combined with blend 1 in the impair absorption of vitamin B is: a gastric acid inhibitor, a blender and blended until Substantially homogenous to gen biguanide, a proton pump inhibitor, an H2 receptor antago erate blend 2. nist. US 2013/013 1007 A1 May 23, 2013 10

17. The method of claim 15, wherein the drug known to impair absorption of vitamin B2 is: metformin, chloramphenicol, methotrexate, or any combi nation. 18. A kit comprising: the composition of claim 1. 19. The kit of claim 18, further comprising instructions for SC.