US20100143533A1 - Nutritional supplement system - Google Patents

Nutritional supplement system Download PDF

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Publication number
US20100143533A1
US20100143533A1 US12/699,798 US69979810A US2010143533A1 US 20100143533 A1 US20100143533 A1 US 20100143533A1 US 69979810 A US69979810 A US 69979810A US 2010143533 A1 US2010143533 A1 US 2010143533A1
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United States
Prior art keywords
vitamin
dosage unit
nutrients
stomach
nutritional supplement
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Abandoned
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US12/699,798
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English (en)
Inventor
Kuei-Tu Chang
Carsten R. Smidt
John Castillo
William J. Mergens
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Shaklee Corp
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Shaklee Corp
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Publication date
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Priority to US12/699,798 priority Critical patent/US20100143533A1/en
Publication of US20100143533A1 publication Critical patent/US20100143533A1/en
Priority to US14/194,528 priority patent/US9248095B2/en
Priority to US14/983,268 priority patent/US9763989B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • Described herein is a nutritional supplement system for the delivery of vitamins, minerals, and/or probiotics for sustaining the health of human subjects.
  • Vitamin and mineral preparations are commonly administered as general nutritional supplements.
  • Micronutrients are elements or compounds which are present in foods and herbs in small or trace amounts. These include vitamins, minerals, or other elements, and substances found in foods.
  • the macronutrients consist of carbohydrates, fats, and proteins, which supply nutrients and calories. Some elements such as calcium, sodium, potassium, chloride, and phosphorus are consumed in relatively large amounts, while many such as iron, iodine, and zinc are consumed in small amounts.
  • Vitamins, such as vitamin B12 and folic acid, and the minerals copper, selenium, and chromium are consumed in very small or trace amounts.
  • probiotic supplements also can be beneficial to the well being of humans. It has been recognized that temporary or chronic digestive symptoms can be caused by a damaged or disordered intestinal flora. Consumption of a nutritional supplement preparation containing suitable microorganisms is often sufficient to alleviate or to eliminate the symptoms caused by a disordered or damaged intestinal flora.
  • probiotics refers to live micro-organisms, delivered in food supplements, which beneficially affect the host animal by improving its intestinal microbial balance. Antibiotics and other related compounds are not included in this definition. ( J. Nutr. 1995; 125:1401-12). For humans, lactobacilli are commonly provided as probiotics, either as single species or in mixed culture with other bacteria. Other genera that have been used are bifidobacteria and streptococci . “Prebiotics” refers to non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of bacteria in the colon.
  • Prior nutritional supplement systems have in some cases delivered nutrients to a location in the digestive tract where, although effective for uptake of the nutrients, have caused user discomfort. In other cases, one or more nutrients are released in a location that is not optimal for uptake by the body. When nutrients or probiotics are released in locations that are unfavorable reduce biological activity can result. For example, probiotics typically do not survive exposure to stomach acid.
  • vitamin B12 is readily absorbed in the last part of the small intestine (ileum), which leads to the large intestine.
  • ileum small intestine
  • the vitamin must combine with intrinsic factor.
  • intrinsic factor As a result of passage through the stomach, vitamin B12 is attaches to intrinsic factor for transfer. This combination of the vitamin and intrinsic factor can then be “caught” by the ileal receptor. Without intrinsic factor, significant amounts of vitamin B12 can remain in the intestine and are excreted in the stool.
  • a nutritional supplement system that supplies nutrients and/or probiotics at various appropriate locations in the digestive tract.
  • One particular element of such a system is a dosage unit formulated to release vitamin B12 over time in both the stomach and the intestines of the upper GI tract.
  • a multi-component oral nutritional supplement system supplies a combination of nutrients and/or probiotics at optimal locations throughout the digestive tract of a human subject for efficient nutrient utilization and user comfort and convenience.
  • An optimal system includes four dosage units, although certain other beneficial systems may include two or three dosage units.
  • a first dosage unit that is formulated to quickly release one or more nutrients in the stomach of a human subject.
  • This dosage unit advantageously includes vitamins and minerals or other dietary supplement ingredients that benefit from release in the stomach and exposure to stomach acid, or are not adversely affected by such release or exposure, and/or properly are dispersed in the stomach for optimal absorption further down in the GI tract.
  • This dosage unit advantageously is in the form of a tablet or caplet formed by compression. The tablet may be coated with a layer containing one or more nutrients that best are delivered in the stomach particularly rapidly.
  • the first dosage unit should not contain substances that are not well tolerated by the stomach or that would be harmed by the acidic environment of the stomach; such substances should be delivered in one of the other dosage units described herein.
  • a second dosage unit is formulated to contain nutrients that do not require release in the stomach and exposure to stomach acid for efficient digestion and absorption, and which may cause tolerance problems (repeating, stomach upset, nausea) or loss in biological activity when released in the stomach.
  • This dosage unit advantageously is used to deliver certain nutritional oils, notably fish oil constituents, other omega-3 fatty acid containing oils, and may also include fat-soluble micronutrients that do not require stomach digestion, such as vitamins A, D, E, and carotenoids.
  • the dosage unit advantageously is a sealed gelatin encapsulation that can pass through the stomach before releasing the encapsulated nutrients.
  • a third dosage unit is formulated to contain water-soluble nutrients and other nutrients that are typically very rapidly absorbed and therefore best delivered by sustained release so as to maintain an elevated concentration in the body over time.
  • This dosage unit is designed to slowly, in generally linear fashion, release one or more water-soluble nutrients. The release of these nutrients is initially in the stomach and continues into the intestines of the upper GI tract.
  • This dosage unit advantageously is formulated to release vitamin B12. The dosage unit also is useful to deliver other B-vitamins and vitamin C.
  • a fourth dosage unit contains nutrients and/or other supplement ingredients such as probiotics that are adversely affected by exposure to stomach acid or stomach digestion, and that should be delivered into the lower parts of the small intestine for full activity in the large intestine.
  • This dosage unit is formulated to protect the probiotic microorganisms from potentially lethal acid exposure during passage of the dosage unit through the stomach.
  • it is in the form of a three-layer capsule.
  • These four dosage units are formulated for administration one time each day, and can be taken substantially simultaneously, to provide complete and appropriately timed delivery of a full range of nutrients and probiotics.
  • All the dosage units of complete daily dose of the nutritional supplement system advantageously are packaged together as a multi-element package so that a user will not need to remember to combine various individual dosage units to make a complete daily dose.
  • certain of the dosage units can be split into two or more tablets, caplets, or capsules.
  • the first dosage unit is in the form of two separate dosage elements, preferably tablets or caplets
  • the second dosage unit is in the form of two separate dosage elements, preferably gel encapsulations.
  • the two first dosage unit elements, the two second dosage unit elements, one third dosage unit element, and one fourth dosage unit element can be provided together, for example in a single blister pack card or strip, so that a user will immediately know that the six elements together are a day's dose.
  • a typical blister pack arrangement will have six attached blister strips, separated by perforated detachment lines, with each strip holding the six dosage elements that together comprise a day's dose.
  • the dosage units advantageously employ various forms of extended release excipients or coatings along with immediate release excipients or coatings to deliver the various vitamins and mineral supplements over various optimum rates of release.
  • a folic acid micro-coating can be employed to release folic acid from the multi-vitamin and mineral supplement within minutes after entry into the stomach.
  • Gel diffusion technology can be used to maximize the intestinal adsorption of vitamins B and C for over twelve hours.
  • Providing fish oil in delayed release capsules results in rapid release in the intestines of upper GI tract, which gives maximum bioavailability and minimum stomach discomfort.
  • a triple layer encapsulation system provides for targeted release of probiotics to the lower GI tract.
  • Nutritional supplement dosage units may employ one or more forms of release, including, without limitation, immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereon.
  • the various types of release can be accomplished using well known procedures and techniques.
  • the time release characteristics for the release of the components may be varied by modifying the composition of layers, including modifying any of the excipients or coatings which may be present. For example, changing the composition or amount of the covering or coating layers may be used to control the release of the components. Similarly, when modified release is facilitated by the inclusion of a specific matrix material, controlling the choice and amount of modified release matrix material utilized may be used to control the release of the active components.
  • the matrix material may be present, either surrounding individual components of the composition or over a layer of the composition, in any amount that is sufficient to yield the desired time release or time lag between release of the components.
  • coating materials suitable for use in the practice include, but are not limited to polymer coating materials, hydrogels and gel-forming materials and hydrophilic polymers.
  • Preferred polymer coating materials are cellulose acetate phthalate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, amino methacrylate copolymers such as Eudragit® RS and RL, polyacrylic acid and polyacrylate and methacrylate copolymers such as Eudragit® S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, and shellac.
  • Preferred hydrogels and gel-forming materials include carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit® RS-PM), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular weight about 5 k-5,000 k), polyvinylpyrrolidone (molecular weight about 10 k-360 k), anionic and cationic hydrogels, polyviny
  • Preferred hydrophilic polymers include polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g.
  • Polyox® Union Carbide
  • plasticisers such as plasticisers, lubricants, solvents and the like may be added to a coating.
  • Suitable plasticisers include for example hydroxylated soy lecithin, acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, propylene glycol, triacetin, citrate, tripropioin, diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, glycerol, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisonony
  • a coating layer may be any suitable modified release matrix material or suitable combination of modified release matrix materials. Such materials are known to those skilled in the art.
  • Modified release matrix materials suitable for the practice of the present invention include, but are not limited to, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose and hydroxypropylcellulose), polyethylene oxide, alkylcelluloses (e.g., methylcellulose and ethylcellulose), polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate and mixtures thereof.
  • the dissolution characteristics of a dosage form can be manipulated not only through the quantity of the excipients in the finished dosage form and size of the finished dosage form, but also by a judicious selection and blending of various molecular weights of a given polymer or polymers, as is known to those skilled in the art.
  • Film coated tablets may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet. This procedure is often done to improve the aesthetic appearance of tablets, but may also be done to improve the swallowing of tablets, to mask an obnoxious odor or taste, or to improve to usual properties of an unsightly uncoated tablet.
  • Compressed tablets for example, without limitation, may be prepared by mixing the components with excipients intended to add binding or disintegration qualities. The mixture is either directly compressed, or granulated then compressed, using methods and machinery quite well known to those in the industry.
  • Example prebiotics include oligosaccharides such as glucose, fructose, xylose, galactose, lactose, mannose, arabinose, D-fucose, L-fucose, rhamnose, Actilight, Biotose, Palatinose, IMO, cellobiose, gentiobiose, laevan, maltodextrin, maltose, melibiose, raffinose, lactose, panorich, melezitose, raftiline, raftilose, stachyose, sucrose, tagatose, xylan, fructooligosaccharide (FOS), galactooligosaccharide (GOS), soy oligosaccharide, lactosucrose, maltooligosaccharide, xylooligos
  • oligosaccharides such as glucose, fructose, xylose, gal
  • the first dosage unit is formulated to contain vitamins and minerals, typically at or near their USFDA Daily Value (DV) level, that best are delivered in the stomach.
  • vitamins and minerals typically at or near their USFDA Daily Value (DV) level, that best are delivered in the stomach.
  • Such nutrients include vitamins, minerals and other dietary supplement ingredients that benefit from release in the stomach and exposure to stomach acid, or that are not adversely affected by such release or exposure, and/or that properly are dispersed in the stomach for optimal absorption further down the GI tract.
  • This dosage unit advantageously is in the form of a tablet or caplet formed by compression of a blend containing vitamins, minerals and appropriate excipients. Because rapid delivery of nutrients is desired, the first dosage unit should be formulated for release in less than one hour, and best within 0.75 hour.
  • the tablet or caplet may be coated with a layer containing one or more nutrients that best are delivered particularly rapidly.
  • the coating will include folic acid (folate) for rapid release.
  • folic acid fluoride
  • folic acid in an outer coating is released more rapidly than when folic acid is contained in the core of a tablet, resulting in increased bioavailability.
  • the first dosage unit optimally is formulated to include:
  • Example formulations of a first nutritional supplement dosage unit, in the form of immediate release tablets, are shown in the following table:
  • Coated tablets were assembled by combining the ingredients to form the blend for a core and compressing the blend to form tablets. The tablets were then coated with a film coating solution. Two such tablets served as one day's dose of the first dosage unit.
  • the second dosage unit is formulated to contain nutrients that do not require release in the stomach and exposure to stomach acid for efficient digestion and absorption, and which may cause tolerance problems (repeating, stomach upset, nausea) or loss in biological activity when released in the stomach.
  • This dosage unit advantageously is used to deliver certain nutritional oils, notably fish oil constituents, other omega-3 fatty acid containing oils, and may also include fat-soluble micronutrients that do not require stomach digestion, such as vitamins A, D, E, and carotenoids.
  • the dosage unit advantageously is a sealed gelatin encapsulation that can pass through the stomach before releasing the encapsulated nutrients.
  • This dosage unit is formulated to pass through the stomach without releasing its contents, notably fish oil, and remain unopened until after it naturally passes into the intestines of the upper GI tract. Release in the stomach can lead to an unpleasant taste caused by repeating fish oil aroma (“fish burp”) in the mouth of a user.
  • fish burp repeating fish oil aroma
  • This dosage form thus advantageously is a soft capsule having a coating resistant to gastric juice to achieve a delayed release of the fish oil in the intestine, advantageously a coating of a polymer such as methacrylic acid. Delayed release can also be accomplished or enhanced by cross-linking of gelatin used to form such a capsule or by providing derivates of starch in the casing of such a capsule.
  • the second dosage unit optimally is formulated to include:
  • Lutein ester suspension 2 mg Lycopene suspension 2.5 mg Vitamin D 3 200 IU Mixed tocotrienols & tocopherols 1 mg Vitamin E (a-tocopherol 140 IU concentrate) Total omega-3 fatty acids 500 mg Gamma tocopherol 25 mg Beta and delta tocopherol 10 mg Silicon dioxide n/a Beeswax n/a Glycerin n/a Gelatin n/a Annatto suspension (Ultrabix n/a 03190) Water n/a Enteric coating (TM29Z19241 n/a Clear) Surelease (E-7-19040) n/a Natural vanillin n/a
  • the nutritional ingredients were mixed to form a fill mixture.
  • Gel mass ingredients were mixed to form a gel mass.
  • Formed halves were injected with the fill mixture and then joined to form capsules.
  • Coating ingredients were mixed to make a coating mixture; and then the formed capsules were coated with the mixture in a tablet coating apparatus. The finished product was then dried.
  • Two of the resulting encapsulations served as one day's dose of the second dosage unit.
  • the third dosage unit is formulated to contain one or more water-soluble nutrients and/or other nutrients that are typically very rapidly absorbed and therefore best delivered by sustained release so as to maintain an elevated concentration in the body over time.
  • Certain rapidly-absorbed, typically water-soluble nutrients are best delivered by sustained release so as to maintain an elevated concentration in the body over time. These include B-vitamins and vitamin C. If given in an immediate release dosage unit, the concentrations of such vitamins in the body rapidly decline after an initial peak. Moreover, the absorptive sites and nutrient uptake mechanisms in the intestinal wall can be overwhelmed by the high intestinal nutrient concentrations caused by immediate release dosage units, which is known to reduce the overall amount that can be taken up by the body. Sustained release dosage units of such vitamins have been used to overcome these problems. But sustained release dosage units of such vitamins have typically excluded vitamin B12 because of the perceived need to deliver an entire dose of vitamin B12 to the stomach so that it can be combined with intrinsic factor.
  • vitamin B12 delivered by sustained release, can result in improved bioavailability of vitamin B12 as compared to immediate release in the stomach.
  • subjects were given a tablet containing 9.8 mg vitamin B1, 11.5 mg vitamin B2, 13.1 mg vitamin B6, 90 ⁇ g vitamin B12 and 518 mg vitamin C.
  • B vitamins ingestion of a comparable immediate-release formulation produced peak plasma concentrations for B1, B2 and B6 at 2 hours post ingestion and at 3 hours for serum vitamin B12. B-vitamin concentrations then declined rapidly from peak concentrations, returning to baseline by 6 hr for B1 and B6 and by 12 hr for B2 and B12.
  • sustained release tablet delivery was found to improve the bioavailability of vitamin C and at least three B-vitamins, including vitamin B12, in comparison to immediate release delivery.
  • the third dosage unit thus is formulated to release vitamin B12 in the stomach and intestines of the upper GI tract, advantageously in an amount that is greater than or at multiple levels of the DV (Daily Value) of vitamin B12. This is accomplished by including vitamin B12 in an amount of from 3 mcg to 500 mcg, with best results at a vitamin B12 amount of from 6 mcg to 500 mcg.
  • Best results for the delivery of vitamin B12 are achieved with a dosage unit that releases vitamin B12, as determined by USP dissolution apparatus at 37° C. at 50 RPM paddle speed in 900 ml of 0.1N HCl, continuously and generally linearly over a period of 6 hours. It is particularly advantageous for the dosage unit to be formulated to allow at least 15% of the vitamin B12 to dissolve in one hour in 900 ml of 0.1N HCl at 37° C. This dosage form, after ingestion by a subject, will sustain plasma levels of the vitamin B12 for a period 12 hours.
  • vitamin B12 is achieved, for example, with third dosage unit tablet of 350 mg to 1500 mg total weight, where the tablet contains 20 mcg to 100 mcg of vitamin B12 and contains 5% to 20% HPMC K100/E15 by weight. Superior results are achieved with tablets having 9.5% to 14% HPMC K100/E15.
  • the third dosage unit also can be used to deliver one or more other water-soluble nutrients, particularly other B-vitamins and vitamin C, advantageously at or above or at multiple levels of their DVs (Daily Values) where applicable.
  • the dosage unit thus advantageously will include 30 mg to 1000 mg of vitamin C, 1 mg to 40 mg of vitamin B1, 1 mg to 40 mg of vitamin B2, 10 mg to 300 mg of niacin, 10 mg to 300 mg of vitamin B5, and 1 mg to 40 mg of vitamin B6.
  • a particularly useful formulation includes from 30 mg to 750 mg of vitamin C, from 25 mg to 400 mg of calcium, from 1 mg to 40 mg of vitamin B1, from 1 mg to 40 mg of vitamin B2, from 10 mg to 300 mg of vitamin B5, from 1 mg to 40 mg of vitamin B6, from 6 mcg to 500 mcg of vitamin B12, from 1 mg to 100 mg of bioflavonoid complex, and from 5 mg to 300 mg of quercetin.
  • the third dosage unit is designed to slowly, in a generally linear fashion, release the one or more of such water-soluble nutrients.
  • the release of the water-soluble nutrients in general should occur in the stomach and small intestine (duodenum, jejunum and ileum).
  • the third dosage unit when a supplement is taken with a meal, as commonly recommended, it takes about 6-12 hours to pass through stomach and small intestine. Therefore release of the water-soluble vitamins from the third dosage unit should extend for at least three hours after ingestion, and advantageously for up to a full twelve hours after ingestion.
  • the third dosage unit also advantageously will be formulated to release vitamin B12 such that plasma levels of the vitamin B12 are sustained for a period of at least 6 hours, with best results achieved when formulated such that plasma levels of the vitamin B12 are sustained during the period of from 30 minutes to 24 hours after ingestion.
  • Tablet contents were mixed, and tablets were formed from the resulting mixture.
  • Coating ingredients were mixed, and the resulting mixture was used to coat the tablets.
  • the fourth dosage unit contains nutrients and/or other supplement ingredients, such as probiotics, that are adversely affected by exposure to stomach acid or stomach digestion and that should be delivered into the lower parts of the small intestine for full activity in the large intestine.
  • nutrients and/or other supplement ingredients such as probiotics
  • This dosage unit is formulated to protect the probiotic microorganisms from potentially lethal acid exposure during passage through the stomach. This can be accomplished using coated or enteric-coated tablets or capsules and other solid dosage delivery forms, where the coating is designed to deliver the ingredients into the lower intestinal tract (ileum and colon).
  • the fourth dosage unit is in the form of layered capsule as described in U.S. Pat. No. 5,478,570.
  • Particularly useful is a triple layer, enteric release encapsulation which protects live probiotic organisms from the acidic gastric environment and releases the organisms in the intestinal tract where they can flourish and provide their health benefits.
  • the inner layer or core contains the probiotic organisms (preferably Lactobacillus acidophilus and Bifidobacterium longum ) suspended in vegetable oil.
  • the middle layer composed of hardened vegetable oil, surrounds and protects the inner layer.
  • the outer layer or primary protective shell is composed of gelatin, pectin and glycerine and provides stability from heat, freezing and acid.
  • the capsule has an outer shell that does not dissolve under pH 4 (at 37° C.) and thus is adapted to pass through the stomach intact. Once the capsule reaches the higher pH environment in the intestines, the outer gelatin shell begins to slowly dissolve, gradually exposing the inner lipid layers. The probiotics are then gradually released by the further action of lipolytic enzymes and the motion of the intestinal tract.
  • the fourth dosage unit optimally is formulated to include:
  • each capsule contained the Lactobacillus acidophilus and Buifodobacterium longum.
  • the core was covered by a layer of the vegetable oil to protect the beneficial bacteria during passage through the stomach.
  • the gelatin was provided as an outer shell over the vegetable oil to provide further protection from the acidic stomach environment.
  • the forth dosage unit can be formed using a sodium alginate-ethylcellulose enteric coating system for soft gelatin capsules.
  • the composition of enteric film basically consists of sodium alginate and ethylcellulose.
  • the sodium alginate is insoluble in acids where the pH of the resulting solution (coating solution) falls below 3.0.
  • the ethylcellulose is insoluble in water, but it is a very good film forming and adhesive polymer while the sodium alginate is a crystalline powder which does not have filming capability.
  • An ethylcellulose coating solution can be formed by processing ethylcellulose in an alkaline aqueous solution (ammonia solution) to form a latex solution, for example, Surelease® coating, by Colorcon, West Point, Pa., USA.
  • a latex solution for example, Surelease® coating, by Colorcon, West Point, Pa., USA.
  • Small ethylcellulose particles (latex) are able to disperse uniformly in a solution for coating applications.
  • the ammonia and water are evaporated and the ethylcellulose latexes are left on the tablet surface. Under heated condition, the latexes then can be annealed together to form a non-water soluble film on the tablet surface.
  • Small molecular sodium alginate can be provided in the ethylcellulose aqueous solution.
  • the sodium alginate will dissolve in the latex alkaline solution to form an enteric coating solution. Once the enteric coating solution is sprayed on the tablets (2-4 percent solid gain), the ammonia and water are evaporated. Ethylcellulose latexes then can be annealed to form a film.
  • the sodium alginate and ethylcellulose sodium alginate-ethylcellulose solid solution
  • the enteric coated tablets will stay intact in the acid condition (pH 2.6) for 6-12 hours. Both sodium alginate and ethylcellulose do not dissolve and will prevent water from penetrating into the core tablet to avoid premature release of the active ingredient. Once the tablets reach the intestine, the film starts to dissolve and the content of tablets are released instantly.
  • the ratio of sodium alginate and ethylcellulose can be varied to control the release pattern and insure an instant, full release in the target physiological site for the best bioavailability.
  • a preferred nutritional supplement system includes vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin C, vitamin D3, vitamin E, vitamin B5, vitamin B6, vitamin B12, vitamin B, vitamin K, lutein, lycopene, omega-3 fatty acids (from fish oil), gamma-tocopherol, silicon, beeswax, calcium, niacin, bioflavonoid complex, quercetin, phosphorus, magnesium, zinc, manganese, boron, copper, beta carotene, trace mineral protein hydrolysate for chromium, molybdenum, nickel, tin, vanadium, boron and selenium, N-acetyl cysteine, spirulena, folate, biotin, iodine, probiotic Acidopholis, and probiotic Bifidus.
  • quercetin from 0 mg to 300 mg of quercetin
  • the supplement system is additionally comprised of from 5 mg to 30 mg of iron.
  • the supplement system is additionally comprised of 100 mcg to 1000 mcg of additional folic acid.
  • a nutritional supplement delivery system particularly well adapted for the delivery of nutrients, consists of the first, second, and third dosage units.
  • a nutritional supplement system, particularly well adapted for the delivery of water-soluble nutrients, consists of the first and third dosage units.

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US20110200570A1 (en) * 2010-02-04 2011-08-18 Copperhead Chemical Company, Inc. Composition and Method for Treating Infections and Promoting Intestinal Health
US8168611B1 (en) 2011-09-29 2012-05-01 Chemo S.A. France Compositions, kits and methods for nutrition supplementation
US8183227B1 (en) 2011-07-07 2012-05-22 Chemo S. A. France Compositions, kits and methods for nutrition supplementation
WO2015157428A1 (fr) * 2014-04-08 2015-10-15 Mayo Foundation For Medical Education And Research Capsule ingérable
US20160073666A1 (en) * 2014-09-16 2016-03-17 New Chapter, Inc. Supplement for a Breastfeeding Woman
WO2016112170A1 (fr) * 2015-01-07 2016-07-14 Corr-Jensen Inc. Compositions et procédés pour améliorer une performance athlétique
US20170071859A1 (en) * 2015-09-16 2017-03-16 Corr-Jensen, Inc. Multi-phase release of sports nutrition and energy drink compositions utilizing lipid particulates
EP3373908A4 (fr) * 2015-11-10 2019-04-24 Probiotech LLC Systèmes d'administration de probiotiques
US11523989B2 (en) 2018-06-22 2022-12-13 Probiotech Llc Method to improve the health of the microbiome in a human gastrointestinal system and multi-chamber probiotic delivery products therefor

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WO2010096564A2 (fr) * 2009-02-19 2010-08-26 Probiohealth Llc Compléments alimentaires contenant des acides gras oméga-3 polyinsaturés et des bactéries probiotiques avec bénéfices gastro-intestinaux et dermatologiques potentiels
WO2011099031A1 (fr) * 2010-02-11 2011-08-18 Zota Health Care Limited Antioxydants actifs pour tous les groupes d'âge
JP2012183063A (ja) * 2011-02-14 2012-09-27 Suntory Holdings Ltd ケルセチン配糖体配合容器詰め飲料
EP2962578A1 (fr) * 2014-06-30 2016-01-06 Richard Hubertus Verheesen Procédé de fourniture d'une pluralité de portions nutritives à un utilisateur et produit d'emballage
CN106535909A (zh) 2014-07-01 2017-03-22 普罗比美国公司 双层双重释放益生菌片剂
US11291683B2 (en) * 2016-04-01 2022-04-05 Access Business Group International Llc Bilayer tablets of B vitamins and process for preparing the same
AU2017370929A1 (en) * 2016-12-09 2019-06-06 Balchem Corporation Essential nutrients and related methods
CN108836948B (zh) * 2018-06-11 2024-04-12 宁波西敦医药包衣科技有限公司 一种利用包衣技术实现营养素可控制释放的产品

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US20110200570A1 (en) * 2010-02-04 2011-08-18 Copperhead Chemical Company, Inc. Composition and Method for Treating Infections and Promoting Intestinal Health
US8853269B2 (en) * 2010-02-04 2014-10-07 Copperhead Chemical Company Inc. Composition and method for treating infections and promoting intestinal health
US8183227B1 (en) 2011-07-07 2012-05-22 Chemo S. A. France Compositions, kits and methods for nutrition supplementation
US8168611B1 (en) 2011-09-29 2012-05-01 Chemo S.A. France Compositions, kits and methods for nutrition supplementation
US8545896B2 (en) 2011-09-29 2013-10-01 Chemo S. A. France Compositions, kits and methods for nutrition supplementation
WO2015157428A1 (fr) * 2014-04-08 2015-10-15 Mayo Foundation For Medical Education And Research Capsule ingérable
US20160073666A1 (en) * 2014-09-16 2016-03-17 New Chapter, Inc. Supplement for a Breastfeeding Woman
WO2016112170A1 (fr) * 2015-01-07 2016-07-14 Corr-Jensen Inc. Compositions et procédés pour améliorer une performance athlétique
US20170071859A1 (en) * 2015-09-16 2017-03-16 Corr-Jensen, Inc. Multi-phase release of sports nutrition and energy drink compositions utilizing lipid particulates
WO2017048859A1 (fr) * 2015-09-16 2017-03-23 Corr-Jensen, Inc. Libération à phases multiples de compositions de nutrition sportive et de boisson énergétique grâce à des particules lipidiques
EP3373908A4 (fr) * 2015-11-10 2019-04-24 Probiotech LLC Systèmes d'administration de probiotiques
US11523989B2 (en) 2018-06-22 2022-12-13 Probiotech Llc Method to improve the health of the microbiome in a human gastrointestinal system and multi-chamber probiotic delivery products therefor

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