Abstract:
The present invention is directed to a novel orally dispersible multi-micronutrient dietary supplement in a tablet dosage form. Use of lipid encapsulated substrates, flavorings, sweeteners and bitter masking agents provides for a dosage that suppresses unpleasant tastes or aftertastes and imparts a pleasant mouth feel when the tablet disperses after being sucked or chewed for several minutes. The combination of lipid encapsulated substrates, oral disintegration and multiple daily dosing schedule provides for improved bioavailability of several crucial micronutrients.

Description:
CROSS REFERENCES 
       [0001]    This application claims priority from U.S. Provisional Application No. 61/548,166, filed on Oct. 17, 2011, the contents of which are hereby incorporated by reference herein. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Globally, vitamin and mineral deficiencies affect up to one third of the population and contribute substantially to disease resulting in an increased susceptibility to infections, promotion of birth defects, impairment of intellectual development, blindness and premature mortality. Nutrient supplementation is an affordable proven method to combat this problem however compliance is a major hurdle that needs to be addressed. 
         [0003]    Oral administration is the most common method for administration of dietary supplements. They are generally provided in a capsule or compressed tablet dosage form that is swallowed whole, disintegrated in the stomach and absorbed throughout the gastrointestinal tract. Potential problems with this delivery form include gagging, choking, gastroesophageal reflux as well as poor absorption of certain vitamins. Elderly, children and young adults are among the populations that often encounter difficulties in swallowing whole tablets or capsules. There is a significant demand for more patient friendly dosage forms. Eliminating the necessity for swallowing oral nutrient supplements would increase compliance and improve the overall health of nutrient deficient patients. 
         [0004]    Fat-soluble nutrients when administered orally and disintegrated in the stomach are only sufficiently absorbed through the intestinal tract in the presence of lipids (fats). This is an additional compliance issue, since most patients do not consume supplements simultaneously with fat containing foods leading to insufficient uptake and poor bioavailability of the lipophilic nutrients. Therefore the presence of lipid carriers as well as prolonged interaction of saliva-dissolved or dispersed fat-soluble nutrients with the oral and esophageal mucosa could potentially lead to increased absorption and bioavailability by reducing first pass metabolism. This phenomenon has been observed for drugs using similar delivery techniques. 
         [0005]    There are claims to inventions that offer alternatives to the solid dosage forms for delivery of nutrient supplements but most do not deliver a significant dose per serving, do not have sufficient stability or lack a suitable level of palatability. 
         [0006]    There is thus a need for a palatable, orally dispersible, multi-micronutrient supplement to increase dosing compliance and overcome nutrient deficiencies in these non-compliant groups. 
       BRIEF SUMMARY OF THE INVENTION 
       [0007]    It is the goal of this invention to provide a multi-micronutrient dietary supplement in an orally dispersible tablet dosage form that is palatable, has acceptable mouth feel and delivers a substantial quantity of nutrients after being sucked or chewed for several minutes. The composition contains lipid encapsulated vitamins and minerals, flavorings, sweeteners and bitter masking agents. The vitamin and mineral components promote overall health and the orally dispersible form makes supplement dosing more enjoyable and therefore users more compliant. The tablets and their ingredients are stable for prolonged periods of time at ambient temperature and humidity and can be stored in a metal, plastic or foil receptacle that is conveniently transported in a pocket, purse or other small personal baggage. The dosage form and dosing schedule provide increased absorption and bioavailability of fat-soluble nutrients including vitamins A, D, E and K by release and dispersion in the saliva and subsequent uptake through oral and esophageal mucosal tissue. The remaining nutrients dissolved or suspended in saliva are swallowed for gastric and post gastric absorption. 
         [0008]    A method of preparing the multi-micronutrient vitamin and mineral dietary supplement in an orally dispersible tablet dosage form is also provided. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0009]    The subject composition contains a lipid encapsulated nutrient blend with excipients including sweeteners(s), flavorings, bitterness masker(s) and diluents/lubricants. The following table (Table 1) indicates the categories of the components and the ranges necessary to yield a pleasant tasting tablet of the composition. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Component 
                 Broad Range (w/w %) 
                 Narrow Range (w/w %) 
               
               
                   
               
             
             
               
                 Sweeteners 
                 70-90 
                 77-83 
               
               
                 Flavorings 
                 1-5 
                   2-3.5 
               
               
                 Bitter Masking Agent 
                 0-3 
                 0.1-1   
               
               
                 Diluents/Lubricants 
                 0-3 
                 0.5-1.5 
               
               
                 Lipid Encapsulated 
                 10-25 
                 13-18 
               
               
                 Nutrient Blend 
               
               
                   
               
             
          
         
       
     
         [0010]    The composition can contain one or a mixture of sweeteners including but not limited to glucose, sucrose, lactose, fructose, galactose, fructooligosaccharide, xylitol, erythritol, arabitol, sorbitol, glycerol, mannitol, maltitol, maltose, lactitol, isomalt , aspartame, isomaltulose, rebaudioside A (Reb-A), steviol glycoside, saccharin, dextrose, maltodextrin, sucralose, tagatose. 
         [0011]    The composition can contain one or a mixture of flavorings including but not limited to peppermint, spearmint, wintergreen, cinnamon, lemon, lime, orange, vanillin, almond, amaretto, anise, apple, apricot, banana, blackberry, blueberry, bubble gum, butterscotch, caramel, cherry, chocolate, coffee, cotton candy, crème de menthe, eggnog, English toffee, grape, licorice, marshmallow, peach, peanut (butter), pecan, pina colada, pineapple, pistachio, praline, pumpkin, raspberry, root beer, strawberry, tangerine, papaya, cappuccino, kiwi, mango. 
         [0012]    The composition can contain one or a mixture of natural or synthetic bitterness blockers/maskers including but not limited to glutamate, inosinic acid, guanylic acid, eriodictyol, ferulic acid, homoeriodictyol, sodium ferulate, sterubin, Virginia Dare Natural Bitter Masker #18886K, Talin, Benecoat, Senomyx S2383, Givaudan Flavors Corp GIV3727and GIV3616. 
         [0013]    The composition can contain one or a mixture of diluents/lubricants to ensure proper tableting including but not limited to talc, silica, vegetable stearin, magnesium stearate or stearic acid. 
         [0014]    The following table (Table 2) indicates the content range for each individual lipid encapsulated nutrient per serving in the vitamin blend: 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Nutrient 
                 Broad Range (US RDI %) 
                 Narrow Range (US RDI %) 
               
               
                   
               
             
             
               
                 Vitamin A 
                  0-200 
                 40-60 
               
               
                 Vitamin B1 
                  0-200 
                  80-120 
               
               
                 Vitamin B2 
                  0-200 
                  80-120 
               
               
                 Vitamin B6 
                  0-200 
                  80-120 
               
               
                 Vitamin B12 
                   0-1000 
                 450-550 
               
               
                 Vitamin C 
                  0-200 
                  80-120 
               
               
                 Vitamin D 
                  0-300 
                 125-175 
               
               
                 Vitamin E 
                  0-300 
                 125-175 
               
               
                 Vitamin K 
                  0-200 
                  80-120 
               
               
                 Vitamin B3 
                  0-200 
                  80-120 
               
               
                 Folic Acid 
                  0-200 
                  80-120 
               
               
                 Biotin 
                  0-100 
                 50-70 
               
               
                 Pantothenic Acid 
                  0-200 
                  80-120 
               
               
                 Iodine 
                  0-200 
                  80-120 
               
               
                 Zinc 
                  0-200 
                  80-120 
               
               
                 Copper 
                  0-200 
                  80-120 
               
               
                 Manganese 
                  0-200 
                  80-120 
               
               
                 Selenium 
                  0-200 
                  80-120 
               
               
                 Chromium 
                  0-200 
                  80-120 
               
               
                 Molybdenum 
                  0-200 
                  80-120 
               
               
                 Co-Enzyme Q10* 
                 0-100 mg 
                 20-40 mg 
               
               
                   
               
               
                 *Given in milligrams because there is no US RDI established for this component 
               
             
          
         
       
     
         [0015]    Nutrient Vitamin A includes but is not limited to one or a combination of alpha carotene, beta carotene, gamma carotene, retnyl acetate, retinyl palmitate, beta-cryptoxanthin. 
         [0016]    Nutrient Vitamin B1 includes but is not limited to one or a combination of thiamin hydrochloride, thiamin nitrate. 
         [0017]    Nutrient Vitamin B2 is riboflavin. 
         [0018]    Nutrient Vitamin B6 includes but is not limited to one or a combination of pyridoxine hydrochloride, pyridoxal 5′-phosphate. 
         [0019]    Nutrient Vitamin B12 includes but is not limited to one or a combination of cyanocobalamine, methylcobalamin, (hydroxycolbalamin). 
         [0020]    Nutrient Vitamin C includes but is not limited to one or a combination of ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, zinc ascorbate, magnesium ascorbate, chromium ascorbate, manganese ascorbate. 
         [0021]    Nutrient Vitamin D includes but is not limited to one or a combination of ergocalciferol (Vitamin D2), cholecalciferol (Vitamin D3). 
         [0022]    Nutrient Vitamin E includes but is not limited to one or a combination of d-alpha-tocopherol, d-alpha-tocopheryl acetate, d-alpha-tocopheryl succinate, dl-alpha-tocopherol, dl-alpha-tocopheryl acetate, dl-alpha-tocopheryl succinate, gamma-tocopherol, mixed tocopherols, TPGS, dl-alpha-tocopheryl nicotinate, mixed tocotrienols, tocopherol phosphate. 
         [0023]    Nutrient Vitamin K includes but is not limited to one or a combination of phytonadione, menaquinones. 
         [0024]    Nutrient Vitamin B3 includes but is not limited to one or a combination of Niacinamide, nicotinic acid 
         [0025]    Nutrient Folic Acid includes but is not limited to one or a combination of folic acid, folate, 5 -methyltetrahydrofolate, 5 -formyltetrahydrofolate, 10-formyltetrahydrofolate, 5, 10-metheylenetetrahydrofolate 5, 10-methenyltetrahydrofolate, 5 -formiminotetrahydrofolate, 5 ,6,7,8-tetrahydrofolate, dihydrofolate and pteroylpolyglutamates thereof. 
         [0026]    Nutrient Pantothenic acid includes but is not limited to one or a combination of pantothenic acid, pantothenol, calcium pantothenate, 4′-phosphopantetheine. 
         [0027]    Nutrient Iodine includes but is not limited to one or a combination of potassium iodide, sodium iodide, iodine, iodine caseinate. 
         [0028]    Nutrient Zinc includes but is not limited to one or a combination of zinc oxide, zinc acetate, zinc gluconate, zinc sulfate, zinc picolinate, zinc orotate, zinc monomethionine, zinc citrate, zinc aspartate, zinc histidine, zinc cysteine. 
         [0029]    Nutrient Copper includes but is not limited to one or a combination of copper oxide, copper picolinate, copper gluconate, copper sulfate, copper glycinate, copper lysinate. 
         [0030]    Nutrient Manganese includes but is not limited to one or a combination of manganese sulfate, manganese gluconate, manganese ascorbate, manganese picolinate, manganese amino acid chelates. 
         [0031]    Nutrient Selenium includes but is not limited to one or a combination of Sodium selenate, selenomethionine, sodium selenite, methylselenocysteine. 
         [0032]    Nutrient Chromium includes but is not limited to one or a combination of chromium picolinate, chromium chloride, chromium nicotinate, chromium citrate. 
         [0033]    Nutrient Molybdenum includes but is not limited to one or a combination of sodium molybdate, ammonium molybdate. 
         [0034]    Co-Enzyme Q10 is a 1,4-benzoquinone, where Q refers to the quinine or quinol chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail. 
         [0035]    Tablets contain from 0.3 to 2.0g, preferably 0.4 to 1.0g, more preferably from 0.5 to 0.8g of the composition and have a diameter of from 0.2 to 1.0″ preferably 0.3 to 0.8″ more preferably 0.4 to 0.6″. 
         [0036]    The number of tablets per serving to deliver a sufficient quantity of nutrients is from 2 to 12 tablets, preferably 3 to 9 tablets and more preferably 5 to 7 tablets. The oral disintegration time of the tablet is from 1 to 12 minutes, preferably 3 to 8 minutes, more preferably 5 to 7 minutes. 
         [0037]    The subject composition can per prepared by combining the sweeteners, flavorings, bitter masking agent and lipid encapsulated nutrient blend in a ribbon blender until thoroughly mixed. A solid diluent is then added and the mixture blended. The mixture is sifted and tableted using a tablet press. 
       EXAMPLES 
     Example 1  
       [0038]    Sorbitol (79.92% w/w), Reb-A (0.27% w/w), natural mint oil (2.4% w/w), vanillin (0.38% w/w), bitter masking agent (0.48% w/w) and the lipid encapsulated nutrient blend (15.55% w/w, see Table 3 for contents) are combined in a ribbon blender and mixed for 5 minutes. Magnesium stearate (1.00% w/w) is added and the mixture is allowed to mix for an additional 2 minutes. The mixture is sifted and tableted into 0.67 g tablets with a diameter of 0.50″. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Nutrient 
                 Source 
                 US RDI % 
                 Content/0.625 g 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Vitamin A 
                 Beta Carotene* 
                 50.00 
                 2500.00 
                 IU 
               
               
                 Vitamin B1 
                 Thiamine Mononitrate 
                 100.00 
                 1.50 
                 mg 
               
               
                 Vitamin B2 
                 Riboflavin 
                 100.00 
                 1.7 
                 mg 
               
               
                 Vitamin B6 
                 Pyridoxine 
                 100.00 
                 2.00 
                 mg 
               
               
                   
                 Hydrochloride 
                   
                   
                   
               
               
                 Vitamin B12 
                 Cyanocobalamin 
                 500.00 
                 30.00 
                 mcg 
               
               
                 Vitamin C 
                 Sodium Ascorbate 
                 56.25 
                 33.75 
                 mg 
               
               
                 Vitamin C 
                 Ascorbic Acid 
                 43.75 
                 26.25 
                 mg 
               
               
                 Vitamin D 
                 Cholecalciferol 
                 150.00 
                 600.00 
                 IU 
               
               
                 Vitamin E 
                 dl-Alpha Tocopheryl 
                 150.00 
                 45.00 
                 IU 
               
               
                   
                 Acetate 
                   
                   
                   
               
               
                 Vitamin K 
                 Phytonadione 
                 100.00 
                 80.00 
                 mcg 
               
               
                 Vitamin B3 
                 Niacinamide 
                 100.00 
                 20.00 
                 mg 
               
               
                 Folic Acid 
                 Folic Acid 
                 100.00 
                 400.00 
                 mcg 
               
               
                 Biotin 
                 Biotin 
                   
                 180.0 
                 mcg 
               
               
                 Pantothenic 
                 Calcium 
                 100.00 
                 10.00 
                 mg 
               
               
                 Acid 
                 D-Pantothenate 
                   
                   
                   
               
               
                 Iodine 
                 Potassium Iodide 
                 100.00 
                 150.00 
                 mcg 
               
               
                 Zinc 
                 Zinc Oxide 
                 100.00 
                 15.00 
                 mg 
               
               
                 Copper 
                 Copper Oxide 
                 100.00 
                 2.00 
                 mg 
               
               
                 Manganese 
                 Manganese Sulfate 
                 100.00 
                 2.00 
                 mg 
               
               
                 Selenium 
                 Sodium Selenate 
                 100.00 
                 70.00 
                 mcg 
               
               
                 Chromium 
                 Chromium Picolinate 
                 100.00 
                 120.00 
                 mcg 
               
               
                 Molybdenum 
                 Sodium Molybdate 
                 100.00 
                 75.00 
                 mcg 
               
               
                 Co-Enzyme Q10* 
                 Co-Enzyme Q10* 
                 * 
                 30.00 
                 mg 
               
             
          
           
               
                 Q.S. 
                 Sodium Ascorbate 
                   
                   
               
               
                   
               
               
                 *No US RDI % established for this component. 
               
             
          
         
       
     
       Example 2 
       [0039]    Sorbitol (79.92% w/w), Reb-A (0.23% w/w), vanillin (0.38% w/w) and bitter masking agent (0.48% w/w) are combined in a ribbon blender and mixed for 2 minutes. Cinnamon (2.4% w/w), hot cinnamon (1.68% w/w) are added to the mixture and blended for 2 minutes. The lipid encapsulated nutrient blend (14.58% w/w, see Table 3 for contents) is added to the mixture and blended for 2 minutes. Magnesium stearate (0.96% w/w) is added and the mixture is allowed to mix for an additional 2 minutes. The mixture is sifted and tabletted into 0.67g tablets with a diameter of 0.50″. 
       Example 3 
       [0040]    Sorbitol (79.73% w/w), Reb-A (0.23% w/w), vanillin (0.38% w/w) and bitter masking agent (0.48% w/w) are combined in a ribbon blender and mixed for 2 minutes. Wintergreen flavor (2.85% w/w) and wintergreen oil (1.90% w/w) are added to the mixture and blended for 2 minutes. The lipid encapsulated nutrient blend (14.48% w/w, see Table 3 for contents) is added to the mixture and blended for 2 minutes. Magnesium stearate (0.95% w/w) is added and the mixture is allowed to mix for an additional 2 minutes. The mixture is sifted and tabletted into 0.67g tablets with a diameter of 0.50″.