WO1992021355A1 - Combinaisons de therapies a base de calcium, d'oligo-elements, de vitamine d et de medicaments - Google Patents

Combinaisons de therapies a base de calcium, d'oligo-elements, de vitamine d et de medicaments Download PDF

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Publication number
WO1992021355A1
WO1992021355A1 PCT/US1992/003995 US9203995W WO9221355A1 WO 1992021355 A1 WO1992021355 A1 WO 1992021355A1 US 9203995 W US9203995 W US 9203995W WO 9221355 A1 WO9221355 A1 WO 9221355A1
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Prior art keywords
calcium
vitamin
diphosphonic acid
bone
malate
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PCT/US1992/003995
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English (en)
Inventor
Mark Benson Andon
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The Procter & Gamble Company
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Publication date
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to SK1326-93A priority Critical patent/SK132693A3/sk
Priority to CS932553A priority patent/CZ281823B6/cs
Priority to KR1019930703623A priority patent/KR100244603B1/ko
Priority to AU19968/92A priority patent/AU666654B2/en
Priority to BR9206072A priority patent/BR9206072A/pt
Priority to JP5500425A priority patent/JPH07502012A/ja
Publication of WO1992021355A1 publication Critical patent/WO1992021355A1/fr
Priority to NO934282A priority patent/NO934282L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds 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
    • A23L33/155—Vitamins A or D
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins

Definitions

  • the present invention relates to nutritional and therapeutic improvements in calcium supplements containing trace minerals, in particular copper, manganese and zinc and vitamin D, estrogen, calcitonin or Didronel or diphosphonate drug therapies. These supplements are useful for increasing bone growth and treating age-related bone loss. They can be used in conjunction with foods and beverages or taken as an oral solid or liquid supplement.
  • the invention also relates to a method of building bone or treating bone loss in osteoporosis patients, post-menopaus- al women and/or elderly men.
  • Vitamin and mineral supplements for human and veteri ⁇ nary use are commonplace. Some diets, heavy physical exercise and disease conditions may require the intake of considerable quantities of minerals and vitamins apart from those generally obtained through what otherwise would be considered a normal diet. Vitamin and mineral supplementa ⁇ tion is important primarily for those who have inadequate diets, including growing children. Older adults have an additional need for calcium to help prevent the bone- loss which occurs as a normal consequence of the aging process. In particular, postmenopausal women need additional calcium due to hormonal changes which can accelerate the bone loss rate leading to a further diminishment in bone mass.
  • the trace minerals which affect bone growth are cop ⁇ per, zinc and manganese. Supplementation of the diet with these minerals along with a highly bioavailable source of calcium is highly desirable. Commercially available miner ⁇ al supplements are useful in many circumstances where increased mineral intake is desirable. Most of these multi-vitamin and multi-mineral tablets are low in calcium, requiring separate supplementation with calcium sources. In addition, not all calcium sources are equal in terms of bioavailability and absorption. The addition of the vita ⁇ min D, calcitonin, estrogen and/or other therapy (editronate or diphosphonates) makes the supplementation more complex since three pills or more could be involved.
  • This invention also relates to methods of building bone in humans and other animals, i.e., for the treatment of age-related bone loss and related disorders.
  • this invention relates to such methods of treatment by administration of certain calcium salts and the miner ⁇ als, copper, zinc and manganese along with vitamin D and/or drug therapy.
  • Calcium is the fifth most abundant element in the human body. It plays an important role in many physiologi ⁇ cal processes, including nerve and muscle functions. Not surprisingly, nutritional and metabolic deficiencies of calcium can have broad-ranging adverse effects. Since about 98% to 99% of the body's calcium is found in bone tissues, many of these adverse effects are manifested through deficiencies in the structure, function and integ ⁇ rity of the skeletal system.
  • Osteoporosis can be generally defined as the reduction in the quantity of bone, either from the reduc ⁇ tion in bone formation or the acceleration of bone resorption, in either event the result is a decrease in the amount of skeletal tissue.
  • primary and secondary there are two types of osteoporosis: primary and secondary.
  • Secondary osteoporosis is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases are idiopathic "primary osteoporosis".
  • Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
  • Bone fractures often occur, for example, in the wrist, hip and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
  • Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. Two reactions are involved, bone loss or resorption and bone growth or accretion. This remodeling occurs in a series of discrete pockets of activity in the bone, C lled “osteoclasts” and “osteoblasts”. Osteoclasts (bone dis ⁇ solving or resorbing cells) are responsible for the resorption of a portion of bone within the bone matrix, during the resorption process. After resorption, the osteoclasts are followed by the appearance of osteoblasts (bone forming cells), which then refill the resorbed por ⁇ tion with new bone.
  • osteoblasts bone forming cells
  • compositions and methods are described in the medical literature for the "treatment” of osteoporosis. See, for example, R. C. Haynes, Jr. et al., "Agents affect ⁇ ing Calcification", The Pharmacological Basis of Therapeutics. 7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); and G. D. Whedon et al., “An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletoqenesis (A. Ornoy et al., Edi ⁇ tors, 1985). Estrogen is often used to affect the metabo ⁇ lism of calcium by influencing the osteoblast cells.
  • Nutritional therapies for osteoporosis have also been proposed. Many calcium-containing compounds and composi ⁇ tions have been described for use as nutritional supple ⁇ ments. Many commercial preparations are also available, typically containing calcium carbonate or calcium phos ⁇ phate. Other calcium salts have also been described for use in calcium supplements, including calcium lactate, calcium citrate and calcium gluconate.
  • German OLS 2,845,570 issued to E.R.E. (Europe Repre ⁇ sentation Establishment, 1980) describes a honey containing composition.
  • Honey contains low levels of calcium, manga ⁇ nese, copper as well as trace amounts of magnesium, iron, phosphorous, silicon and nickel.
  • the value of honey as a medicant is undisputed according to this patent applica ⁇ tion.
  • This application claims a honey containing composi ⁇ tion with levarotatory ascorbic acid and citric acid.
  • This patent has issued as US 4,243,794 (1981).
  • US 4,497,800 issued to Larsen et al (assigned Mead Johnson & Company, 1985) describes a nutritionally complete ready-to-use liquid diet for providing total patient nour ⁇ ishment.
  • the diet contains free a ino acids and small peptides, a carbohydrate source, and nutritionally signifi ⁇ cant amounts of all essential vitamins and minerals, and stabilizers.
  • the minerals include calcium, copper, zinc and manganese, among others. Most of these minerals are given as the gluconate salt.
  • US 3,992,555 issued to Kovacs (assigned Vitamins, Inc., 1976) describes food supplements prepared by mixing assimilable iron compounds, vitamins and minerals with a heated edible fat carrier.
  • the minerals include calcium, zinc, copper, and manganese among others.
  • US 3,950,547 issued to Lamar et al (assigned Syntex Inc, 1976) describes a dietary composition containing peptides and/or amino acids, lipids and carbohydrates in an aqueous emulsion. Suitable minerals for adding at low levels include among others calcium, copper and zinc.
  • Hungerford et al "Interaction of pH and ascorbate in intestinal iron absorption," (1983) describes the iron absorption from various food materials.
  • the diet which was low in iron also contained calcium carbonate, manganese sulfate and copper sulfate among others.
  • the supplements employ specific calcium salts of mixtures of citric and malic acids.
  • the drug and/or 0 vitamin therapies which they are combined with include vitamin D, Didronel (diphosphonates) and calcitonin.
  • the mineral supplements comprise zinc, copper and manganese. Estrogen can be used in conjunction with any of these therapies. 5
  • the present invention provides methods for building bone in a human or other animal subject, comprising admin ⁇ istering to said subject a safe and effective amount of vitamin D, didronel, estrogen and/or calcitonin, along with calcium citrate malate and copper, zinc and manganese salts.
  • the calcium citrate malate comprises a complex or a mixture of calcium salts having a ratio of moles citrate to moles malate of from about 1:0.16 to about 1:13.5.
  • the combination of these minerals and drugs is preferably administered in an oral dosage form, containing pharmaceu- tically-acceptable carriers and excipients.
  • the present invention relates to stable miner ⁇ al/vitamin and/or drug supplements and supplemented foods and beverages including dry beverage mixes and to a method of building bone.
  • the term “comprising” means various components can be conjointly employed in the mineral sup ⁇ plements, foods and beverages of the present invention. Accordingly, the terms “consisting essentially of” and “consisting of” are embodied in the term comprising.
  • nutritional or “nutritionally-supplemental- amount” herein is meant that the mineral and vitamin sourc ⁇ es used in the practice of this invention provide a nour ⁇ ishing amount of the trace minerals, calcium and vitamin D. This is supplemental or in addition to the amount found in the diet. This supplemental amount will comprise at least 25% of the Recommended Dietary Allowance (RDA) of the daily intake of calcium, copper, manganese, zinc and vitamin D. Preferably, at least 50% of the Recommended Dietary Allow ⁇ ance (RDA) will be provided.
  • RDA Recommended Dietary Allowance
  • the RDA for minerals and vitamins is as defined in The United States of America (see Recommended Daily Dietary Allowance-Food and Nutrition Board, National Academy of Sciences-National Research Council).
  • a "pharmaceutically accept ⁇ able" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • the term "safe and effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic re ⁇ sponse) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the specific "safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
  • flavors includes both fruit and botanical flavors.
  • sweeteners includes sugars, for example, glucose, sucrose, and fructose. Sugars also include high fructose corn syrup solids, invert sugar, sugar alcohols, including sorbitol, and mixtures thereof. Artificial sweeteners are also included in the term sweet ⁇ ener.
  • trace minerals means cop ⁇ per, manganese and zinc. These minerals play an important role in nutrition, but are required in only small or trace amounts in the diet. All three of these minerals are important enzymatic cofactors which are essential in devel ⁇ opment of bone in animals and humans.
  • the trace minerals herein are administered in the form of pharmaceutically acceptable salts.
  • the "carboxylate counterion" used in the preparation of the preferred mineral salts herein can be any ingestible carboxylate species. However, some judgement must be made with regard to flavor contribution. For example, citrate, malate and ascorbate yield ingestible complexes whose flavors are judged to be quite acceptable, particularly in fruit juice beverages. Tartaric acid is acceptable, par ⁇ ticularly in grape juice beverages, as is lactic acid. Longer-chain fatty acids may be used in solid mineral supplements, but can affect flavor and water solubility. For essentially all purposes, the malate (preferred), gluconate, citrate and ascorbate moieties suffice, although others can be selected, according to the desires of the formulator.
  • the counterion for the trace minerals can also be phosphate, chloride, sulfate, nitrate or the like. Howev ⁇ er, these inorganic counterions can undesirably interact with calcium ions, especially in beverages. In high con ⁇ centrations, these counterions, particularly chloride and sulfate, may contribute an undesirable flavor note to the supplement, food, or beverage containing them. Accordingly, the carboxylate counterions noted above are preferred herein.
  • Calcitonin is a 32 amino acid protein produced by the thyroid C cells in higher mammals. It is known to block the stimulatory effects of PTH and other humoral agents on bone resorption. Calcitonin therapy decreases the rate of bone loss in osteoportoic patients. It is also used to treat Paget's disease of the skeleton and is used in combi ⁇ nation with ethane dihydroxy diphosphonate. As used here ⁇ in, the term calcitonin includes thyrocalcitonin, whether natural or synthetic.
  • Vitamin D Vitamin D includes vitamin D, cholecalciferol (D3), ergocalciferol (D2) and its biolofically active metabolites and precursors such as, l ⁇ , 25-(OH)2 vitamin D; 25 OH vitamin D, its biologic precursor; and l ⁇ hydroxy vitamin D, and analogues of the dihydroxy compound.
  • D3 cholecalciferol
  • D2 ergocalciferol
  • these ateri- als promote intestinal absorption of calcium, contribute to plasma calcium regulation by acting on bone density and stimulate reabsorption of calcium by the kidney.
  • Didronel It is the disodiu salt of 1-hydroxyethylidene diphosphonic acid (EHDP or editronate). It and other related diphosphonates and amino diphosphonates are collec ⁇ tively referred to herein as "diphosphonates”.
  • Didronel and the diphosphonates act primarily on the bone. They inhibit the formation, growth and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Generally, they do not adversely effect the levels of parathyroid hormones or calcium.
  • Bone-active drugs which are pharmaceutically-accept- able salts of amine-functional compounds include pharmaceu ⁇ tically-acceptable salts of amine-functional diphosphonate drug compounds and phosphonoalkylphosphinate drug com ⁇ pounds, including the prodrug esters thereof.
  • Such com ⁇ pounds are disclosed, for example, in U.S. Patent Nos. 3,683,080 issued to Francis on August 8, 1972; 4,304,734 issued to Jary, Rihakova & Zobacova on December 8, 1981; 4,687,768 issued to Benedict & Johnson on August 18, 1987; 4,711,880 issued to Stahl & Schmitz on December 8, 1987; and 4,719,203 issued to Bosies & Gall on January 12, 1988; copending U.S. patent application Serial Nos.808,584*, of
  • Bone-active drugs more preferred in compositions of the present invention include pharmaceutically-acceptable salts of the following compounds or esters thereof: 6-amino-l- hydroxy-hexane-l,l-diphosphonic acid, 4-amino-l-hydroxy- butane-l,l-diphosphonic acid, N,N-dimethyl-4-amino-l- hydroxy-butane-1,1-diphosphonic acid,
  • N,N-diethyl-4-amino-l-hydroxy-butane-l,l-diphosphonic acid 3-amino-l-hydroxy-propane-l,l-diphosphonic acid, N,N-dimethyl-3-amino-l-hydroxy-propane-l,l-diphosphonic acid; N,N-diethyl-3-amino-l-hydroxy-propane-1,1-diphos- phonic acid, 6-aminohexane-l,l-diphosphonic acid, phenyla- minomethane diphosphonic acid, N,N-dimethylaminoethane diphosphonic acid, N-(2-hydroxyethyl)-aminomethane diphos ⁇ phonic acid, N-acetylaminomethane diphosphonic acid, 3-(2- acetylaminocyclohexyl)-l-hydroxypropane-1,1-diphosphonic acid, 2 -(2-aminomethylcyclohe
  • N-(4'-piperidinyl)-amino-methane diphosphonic acid 0 N-(2'-(3'-methyl)-piperidinylidene)-amino-methane diphosphonic acid; N-(2'-(5'-methyl)-piperidinylidene)- amino-methane diphosphonic acid; 2
  • Bone-active drug compounds which are more preferred still in compositions of the present invention include pharmaceutically-acceptable salts of the following compounds or esters thereof: 6-amino-l-hydroxy-hexane-l,l-diphosphonic acid, 3-amino-l-hydroxy-propane-l,l-diphosphonic acid, octahydro-l- ⁇ yridine-6,6-diphosphonic acid, 2-(2'-piperi- dinyl)-ethane-l,l-diphosphonic acid; 2 -(3'-piperidinyl)-ethane-l,l-diphosphonic acid; 2 -(2'-piperidinyl)-l-hydroxy-ethane-l,l-diphosphonic acid; 2-(3'-piperidinyl)-l-hydroxy-ethane-l,l-diphosphonic acid; N-(2'-(3'-methyl)-piperidinylidene)-amino-methane dip
  • compositions of the present invention include the phosphonomethyl phosphinic acid compounds which are analo ⁇ gous to the above diphosphonic acid compounds.
  • a "pharmaceutically-acceptable salt of an amine-functional compound” means a salt of addition of the compound having similar pharmacological activity (effi ⁇ cacy and safety) to the base form of the compound.
  • a salt of addition of a compound has substantially the same pharmacological activity as the base form of the compound.
  • a salt of addition of a compound can be formed by the association of an amine-functional drug compound in its base form with an appropriate acid.
  • Acids known to form pharmaceutically-acceptable salts of addition with base forms of certain amine-functional drug compounds include, but are not limited to, the following: hydrochlo ⁇ ric, hydrobro ic, hydriodic, maleic, succinic, tartaric, fumaric, lactic, citric, ascorbic, oxalic, gluconic, phos ⁇ phoric, nitric, sulfuric, methane sulfonic, ethane sulfonic and 2-naphthalene sulfonic.
  • Estrogen Estrogen therapy can be used along with any of these regimens.
  • the method herein also comprises coadministering from about 0.3 mg to about 6 mg of estrogen along with the calcium and trace minerals and vitamin D, calcitonin or editronate (or diphosphonates). Preferably from 0.625 mg to about 1.25 mg of estrogen is taken daily. Any viable estrogen hormone replacement can be used.
  • Calcium Trace Mineral Component In supplements of the type disclosed herein, the nutritionally supplemental amount for the minerals will generally comprise more than 50% of the RDA and preferably 80%-100% RDA, most preferably 100% of the RDA, per unit portion of the finished supplement. Of course, it is recognized that the preferred daily intake of any mineral may vary with the user.
  • the RDA (calcium) will range from 360 mg per 6 Kg for infants to 800 mg/54-58 Kg female, depending somewhat on age. Moreover, it can be difficult to supple ⁇ ment beverages with more than 20-30% RDA of calcium (based per serving) without encountering precipitation and/or organoleptic problems. However, this level of supplementa ⁇ tion is equivalent to cow's milk in calcium value, and is therefore acceptable.
  • the recommended dietary allowance for zinc is 15 milligrams (mg) per day for males and 12 mg per day for females. There is no specific RDA for manganese and cop ⁇ per. A safe and adequate range has been established as 2 to 5 mg for manganese and for copper, the range is 1.5 mg to 3 mg per day.
  • Any soluble salt of the trace minerals can be used, for example, zinc chloride, zinc sulfate, manganese sulfate, manganese gluconate, copper sulfate and copper gluconate are useful. A nutritionally supplemental amount of these minerals is used. However, the particular salt used and the level will depend upon their interaction with other supplement ingredients.
  • Inorganic anions which are useful for making the trace mineral salts are sulfate, nitrate, phosphate, hydrogen phosphate and carbonate.
  • Organic anions include carboxylate anions, e.g. citrate, malate tartrate, acetate and glyconate.
  • the methods of this invention involve administration of a mixture of calcium salts, herein "calcium citrate malate,” comprising calcium salts of citric acid and malic acid.
  • the calcium citrate malate may consist of a mixture of calcium citrate and calcium malate, a complex of calcium containing citrate and malate ligands, a mixture of a calcium salt with citric acid and malic acid, or combina ⁇ tions thereof.
  • Mixtures of a calcium salts and citric and malic acids may be used to form calcium citrate malate in situ, the beverage.
  • Preferred are calcium citrate malate mixtures made by adding calcium carbonate, calcium hydroxide or other suitable source to a mixture of citric and malic acids.
  • the molar ratio of citrate:malate is from about 1:0.16 to about 1:13.5, preferably from about 1:0.5 to about
  • the ratio of moles calciunutotal moles citrate:total moles of malate is from about 2:1:1 to about 8:2:1, preferably from about 4:2:3 to about 6:3:4.
  • the calcium citrate malate may
  • Such anions may include, for example, carbonate, hydroxide, phosphate and mixtures thereof depending on the calcium source.
  • the calcium citrate malate is neutral, 5 comprised entirely of citrate and malate anions.
  • the equivalents of calcium (2 x moles calcium) is about equal to the total number of equivalents of citrate (3 x moles citrate) plus malate (2 x moles malate).
  • a preferred calcium citrate malate has a calci-
  • the calcium citrate malate used in the methods of this invention may be provided in solid or liquid forms. Calcium citrate malate for use in solid forms may be made, for
  • Calcium carbonate can be used as the calcium source.
  • Other sources include calcium oxide and calcium hydroxide.
  • Calcium chloride, calcium phosphate and calcium sulphate are suitable for use herein, but they can form an acid solution which could adversely affect the flavor of bever ⁇ ages and water solutions of the calcium citrate malate.
  • a solid forms during the mixing of the calcium oxide or calcium hydroxide with the citric and malic acid. When these materials are used, it is necessary to mix the solu ⁇ tion until all of the calcium appears to have dissolved. The calcium citrate malate ligand will precipitate when its solubility is exceeded.
  • the preferred method of preparation is to prepare a highly concentrated solution of the calcium citrate malate which quickly and efficiently forces metastable calcium citrate malate out of solution. Concentrations of from 20% to 75% are preferred. Preferably the concentration is from 40% to 65%.
  • the reaction temperature can be ambient (20°C) or higher.
  • the temperature of the reaction is in the range of 30°C to 80°C. Most preferably it is from 40°C to 60 C.
  • Flavor Component The flavor component of the present nvention contains flavors selected from natural flavors, bot ical flavors and mixtures thereof.
  • flavors refers to those flavors derived from the edible reproductive part of a seed plant, especially one having a sweet pulp associated with the seed.
  • fruit fla ⁇ vor also included within the term “fruit fla ⁇ vor” are synthetically prepared flavors made to simulate fruit flavors derived from natural sources.
  • Botanical flavor refers to flavors derived from parts of a plant other than the fruit; i.e. derived from bean, nuts, bark, roots and leaves. Also included within the term “botanical flavor” are synthetically pre ⁇ pared flavors made to simulate botanical flavors derived from natural sources. Examples of such flavors include cocoa, chocolate, vanilla, coffee, kola, tea, and the like. Botanical flavors can be derived from natural sources such as essential oils and extracts, or can be synthetically prepared.
  • flavor enhancing can depend upon the flavor(s) select ⁇ ed, the flavor impression desired, and the form of the flavor component.
  • the flavor component can comprise at least 0.05% by weight of the beverage composition and preferably from 0.05% to about 10%.
  • the amount of flavor added to the food, beverage or supplement is within the skill of one in the art and depends on the flavor intensity desired.
  • the amount of flavor added is from about 0.05% to about 20%.
  • Lower levels of artificial or synthetic chocolate flavors are used than for cocoa itself.
  • Beverages can be flavored with fruit or other botani ⁇ cal flavors, e.g., vanilla, strawberry, cherry, pineapple, banana, and mixtures thereof.
  • fruit or other botani ⁇ cal flavors e.g., vanilla, strawberry, cherry, pineapple, banana, and mixtures thereof.
  • the calcium, citric and malic acids can be added with the trace minerals and vitamin D to a 100% fruit juice or a diluted fruit juice.
  • the sugars present in the juice are useful sweeteners, and the juice can be the flavor compo ⁇ nent.
  • Such beverages can contain from 5% to 100% juice.
  • Preferably dilute juice beverages will have from 10% to 40% juice.
  • Preferred juices for 100% juice products or diluted products are orange, cranberry, apple, pear, grape, rasp ⁇ berry, lemon, grapefruit, pineapple, banana, blackberry, blueberry and passion fruit juices and mixtures thereof.
  • the sweetener composition is usually a monosaccharide or a disaccharide. These include sucrose, fructose, dex ⁇ trose, maltose and lactose. Other carbohydrates can be used if less sweetness is desired. Mixtures of these sugars can be used.
  • sugar of the present invention can contain other natural or artificial sweeteners.
  • suitable sweeteners include saccharin, cyclamates, acetosulfam, L-aspartyl-L-phenylalanine lower alkyl ester sweeteners (e.g. aspartame), L-aspartyl-D-alanine amides disclosed in U.S. Patent 4,411,925 to Brennan et al., issued October 23, 1983, L-aspartyl-D-serine amides dis ⁇ closed in U.S. Patent 4,399,163 at Brennan et al., issued August 16, 1983, L-aspartyl-L-1-hydroxymethyl- alkaneamide sweeteners disclosed in U.S.
  • Patent 4,338,346 to Brand issued December 21, 1982, L-aspartyl-1-hydroxyethyl- alkaneamide sweeteners disclosed in U.S. Patent 4,423,029 to Rizzi, issued December 27, 1983, L-aspartyl-D- phenylglycine ester and amide sweeteners disclosed in European Patent Application 168,112 to J. M. Janusz, pub ⁇ lished January 15, 1986, and the like.
  • a particularly preferred sweetener is aspartame.
  • the amount of the sweetener effective in the food, beverage, mixes or supplements of the invention depends upon the particular sweetener used and the sweetness inten ⁇ sity desired. For noncaloric sweeteners, this amount varies depending upon the sweetness intensity of the par ⁇ ticular sweetener. For sugar (i.e., sucrose), this amount can be from 10% to 85% (typically from 55% to 70%) by weight. In determining the amount of sugar, any sugar or other sweetener present in the flavor component is also included. Low-calorie sweetener combinations containing a noncaloric sweetener such as aspartame and a sugar, such as corn syrup solids, or sugar alcohols can also be used in beverage mixes. In general, the amount of sweetener will be from about 0.5% to about 85%.
  • ingredients Other minor ingredients are frequently included in supplements, foods and beverages. Such ingredients include preservatives such as benzoic acid and salts thereof, sulfur dioxide, butylated hydroxyanisole, butylated hydroxytoluene, etc. Also, typically included are colors derived either from natural sources or synthetically pre ⁇ pared.
  • Salt e.g. sodium chloride
  • other flavor enhancers can be used to improve the flavor of the food, beverage or supplement.
  • Emulsifiers can also be included. Any food grade emulsifier can be used. Lecithin is a preferred emulsifi- er. Other edible emulsifiers include mono- and diglycerides of long chain fatty acids, preferably saturat ⁇ ed fatty acids, and most preferably, stearic and palmitic acid mono- and diglycerides. Propylene glycol esters are also useful in beverage mixes.
  • the pH of the beverages and beverage concentrates of the present invention is dependent upon the weight ratios of the acids, the total amount of acids and the sourness impression desired. Typically, the pH can range from 2.5 to 6.5. Preferred carbonated beverages have a pH of from 3.0 to 4.5.
  • beverage ingredients are frequently in ⁇ cluded in beverages and concentrates.
  • colors derived either from natural sources or synthetically prepared See L. F. Green, Developments in Soft Drinks Technology. Vol. 1 (Applied Science Publishers Ltd. 1978), pp. 185-186 (herein incorporated by reference) for preservatives and colors used in beverages.
  • Beverage Preparation The beverages and concentrates of the present inven ⁇ tion can be prepared by standard beverage formulation techniques. It should be understood, however, that carbon ⁇ ated beverage making techniques, when appropriately modi ⁇ fied, are also applicable to noncarbonated beverages. Also, while the following description is with reference to sugar containing beverages, diet beverages containing noncaloric sweeteners can also be prepared by appropriate modification. Beverages can include dry beverage mixes
  • a beverage concentrate is usually formed containing from 30 15 to 70% by weight water.
  • This beverage concentrate typical ⁇ ly contains the emulsified or water-soluble flavors, emul ⁇ sion stabilizing agents, and weighting agents if needed, any color desired and suitable preservatives. After the concentrate is formed, sugar and water are then added to
  • the water mixed with the beverage syrup or into the drink ⁇ able diluted beverage to achieve carbonation can be sealed in a container such as a bottle or can. See L.F. Green, Developments in Soft Drinks Technology. Vol. 1, (Applied Science Publishers Ltd. 1978), pp. 102-107 (herein 0 incorporated by reference), for a further description of beverage making, in particular the process for carbonation.
  • carbonated beverages of the ' present invention contain from 1.0 to 4.5 volumes of carbon dioxide.
  • Preferred carbonated beverages contain from 2 to 3.5 volumes of carbon dioxide.
  • the calcium source and the acids can be added at various points in these pro ⁇ Waits.
  • the calcium source and acids are preferably added at the same point in this process, but can also be added at different points.
  • the calcium source and acids are included during preparation of the beverage concentrate or beverage syrup.
  • the trace minerals are added after the calcium and acid source have been mixed in.
  • Vitamin D can be added with the oil flavors or weighting oil.
  • a typical formula for chocolate mixes is: a) from 0% to 25% milk solids, preferably from 5% to 20% non-fat milk solids; b) from 0.05% to 20% flavor, preferably cocoa; c) from about 0.5 to about 85% sweetener, preferably sucrose; and d) from about 0.6% to about 0.15% calcium citrate malate and from about 0.60 to about 30 micrograms vitamin D.
  • Solid forms include tablets, capsules, granules and bulk powders. Tablets may contain suitable binders, lubri ⁇ cants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emul ⁇ sions, suspensions, solutions and/or suspensions reconsti ⁇ tuted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid oral dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, and coloring and flavoring agents.
  • a preferred liquid dosage form contains calcium citrate malate and the trace minerals in a juice-containing beverage or other beverage.
  • the trace minerals, calcium citrate malate, vitamin D and/or and drug therapy can be coadministered in one tab ⁇ let, liquid, food or beverage or they can be administered separately.
  • a capsule containing the trace mineral salts, a second tablet with the calcium citrate malate and a third containing vitamin D and/or drug therapy are easy to formu ⁇ late and to swallow.
  • a mineral and vitamin D supplement could also be coadministered with a calcium beverage.
  • Patent 3,903,297, Robert, issued September 2, 1975 Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references; 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition. (1976).
  • Various oral dosage forms of calcium citrate malate, trace minerals, vitamin D and/or drug therapies may be used in the present invention.
  • Such dosage forms comprise a safe and effective amount of calcium citrate malate, trace minerals, vitamin D and/or drug therapies and a pharmaceu ⁇ tically acceptable carrier.
  • the pharmaceutical ⁇ ly acceptable carrier is present at a level of from about 0.1% to about 99%, preferably from about 0.1% to about 75%, by weight of the composition.
  • Unit dosage forms i.e., dosage forms containing an amount of calcium citrate malate suitable for administration in one single dose, according to sound medical practice
  • Unit dosage forms of copper (on an elemental basis) contain 0.5 to 5 mg, preferably 0.5 to 4.0 mg, of manganese (on an elemental basis) contain 1 to 8 mg and preferably from 2 mg to 7 mg, and of zinc (on an elemental basis) contain 1.5 to 30 mg and preferably 7.5 to 20 mg zinc.
  • calcium citrate malate is administered, per day. More preferably, from about 250 milligrams to about 1500 milligrams, most prefer ⁇ ably from about 350 milligrams to about 1000 milligrams, of calcium are administered, per day.
  • the specific amount of calcium citrate malate to be administered depends upon the relative percentage weight of calcium in the particular calcium citrate malate employed.
  • the recommended daily allowance for vitamin D is 200-400 IU depending on age of the subject.
  • the supple ⁇ ments used herein have a unit dosage amount of from about 25 IU to about 1000 IU or from about 0.6 to 25 micrograms.
  • the effective amount of calcitonin is about 100 IU per day. From about 25 IU to 120 IU can be administered with the calcium citrate malate, trace minerals and vitamin D.
  • the effective amount of diphosponate is from about 200 mg to about 1000 mg.
  • the usual safe and effective amount of Didronel and the diphosphonates is from 1 mg/kg/day to 20 mg/kg/day. Preferably from 5 to 10 mg/kg/day are used. This dose can be administered in 2 dosage units, one in the morning and 1 in the evening. Didronel and the bisphosphonates for treatment of age-related bone loss are typically administered in an intermittent cyclical fashion.
  • the present invention provides a method for building bone in a human or other animal subject, comprising administering to said subject a safe and effec ⁇ tive amount of calcium citrate malate, and copper, zinc and manganese and vitamin D and/or either calcitonin, editronate or estrogen for a period of time sufficient to achieve an increase in the net skeletal mass of said sub ⁇ ject.
  • building bone refers to a decrease in the net skeletal loss of bone of the subject treated and therefore a net skeletal increase in mass. The slowing of the rate of bone loss and the increase in growth rate occur simultaneously so the net bone density may stay the same.
  • the increase in mass may be at any skeletal site, including spine, hip, long bones of arms or legs or in the whole skeleton.
  • the net skeletal mass is increased by at least about 0.1%, more preferably at least about 1%.
  • the loss of bone is cumulative over a long period of time.
  • lifetime loss in bone mass is about 35% in males and 50% in females.
  • administering refers to any method which, in sound medical practice, delivers the vitamin D and/or drug, calcium citrate malate and trace minerals used in this invention to the subject to be treated in such a manner so as to be effective in the building of bone.
  • the specific period of time sufficient to achieve an increase in the net skeletal mass of the subject may depend on a variety of factors. Such factors include, for exam ⁇ ple, the specific mineral formulation employed, the amount of minerals administered, the age and sex of the subject, the specific disorder to be treated, concomitant therapies employed (if any), the general physical health of the subject (including the presence of other disorders), the extent of bone loss in the individual, and the nutritional habits of the individual. Although the administration of even small quantities of calcium citrate malate, trace minerals, vitamin D and/or drug therapy may build bone, the net increase in bone mass may not be detectable for short periods of administration.
  • the calci ⁇ um citrate malate, trace minerals and vitamin D, and/or calcitonin or bisphosphonates or estrogen are administered according to sound medical practice for at least about six
  • the methods of this invention may be employed in the treatment of any of a variety of disorders in which the 1 building of bone is desired.
  • the human or other animal "subject" of the methods of this invention is "in need” of a method for building bone, i.e., the subject has a disorder for which building of bone or de ⁇ crease in rate of bone resorption would be advantageous
  • disorders in ⁇ clude, for example, bone fractures, reduced bone mass and disorders typified by bone loss, such as age-related bone loss and osteoporosis (both primary and secondary forms).
  • a preferred method of this invention is for the treat- ⁇
  • Example I illustrates compositions of the type provided by the practice of this invention, but is not intended to be limiting thereof.
  • Example I Several post-menopausal women are treated by adminis ⁇ tering a composition containing calcium citrate malate having a molar calcium:citrate:malate composition of about 6:2:3.
  • the calcium citrate malate is made by first dis ⁇ solving approximately 384.2 grams of citric acid and ap- ⁇ proximately 402.3 grams of malic acid in approximately 2 liters of water. This citrate/malate solution is then heated to approximately 55°C (131°F), with stirring. Separately, approximately 600.6 grams of calcium carbonate is added to approximately 1.2 liters of water, forming a slurry, with stirring.
  • citrate/malate solution is then removed from its heat source, and the calcium carbonate slurry is added slowly, with stirring. The rate of addition is controlled, to contain the reaction as carbon dioxide is released. An additional quantity of water, approximately 0.4 liters, is
  • the excess reaction liquid is filtered off.
  • the calcium citrate malate is dried, for approximately 12 hours at approximately 105°C (221°F), reducing the moisture level to less than about 1%.
  • the dried product is then milled to approximately 10-20 mesh size, for a swallowable tablet
  • Each tablet contains 250 mg.
  • the swallowable tablet dosage form is then made, comprising:
  • the tablet formulation is made by thoroughly admixing 0 the powders, and tabletting using a standard tablet press, to form tablets weighing approximately 1104 milligrams. The tablets are then coated, using a pan coater.
  • the coating solution contains approximately 11% hydroxypropyl ethyl cellulose, approximately 2% 5 polyethylene glycol, approximately 3.5% colorant, and the balance of water.
  • a capsule containing 15 mg zinc (from zinc sulfate), 5 mg manganese (from manganese gluconate) and 2.5 mg copper (from copper gluconate) and 10 micrograms of vitamin D is also administered to each patient.
  • Example II A powdered mineral supplement comprising 2000 gm of calcium citrate malate, 6.3 mg of copper sulfate (2.5 mg copper), 31.3 mg of zinc chloride (15 mg zinc) and 5 mg of manganese (15.4 mg of manganese sulfate monohydrate) is prepared by tabletting the mixture of powders. This tablet is taken in a daily spasin with 2 mg/kg of Didronel for 6 months.
  • Example III A tablet containing 200 mg calcium (from calcium citrate malate), 1 mg copper (from copper gluconate), 1.5 mg manganese (from manganese gluconate), 3 mg zinc (from zinc gluconate), and 3 micrograms vitamin D (from cholecalciferol) is taken 4 times daily along with a single tabletted dose of 0.625 mg conjugated estrogen taking once daily for 2 years.

Abstract

Sont décrits des suppléments de substances minérales nutritionnelles comprenant du citrate-malate de calcium, des sels de manganèse, de cuivre et de zinc et un élément ou des éléments sélectionnés dans le groupe de la vitamine D ou ses métabolites ou précurseurs, et des thérapies à base de médicaments constitués de calcitonine, éditronate, diphosphonates et aminodiphosphonates. Un oestrogène peut également être utilisé avec ces suppléments. Ces suppléments qui fournissent au moins 25 % des taux recommandés d'éléments nutritifs en calcium, d'oligo-éléments et de vitamines, sont utilisés comme additifs au régime normal. Ces éléments permettent d'augmenter la croissance osseuse et de traiter la dégradation osseuse due au vieillissement chez l'homme et l'animal. Ces suppléments peuvent se trouver sous forme de comprimés solides de formes galéniques unitaires liquides ou de boisson.
PCT/US1992/003995 1991-05-28 1992-05-15 Combinaisons de therapies a base de calcium, d'oligo-elements, de vitamine d et de medicaments WO1992021355A1 (fr)

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SK1326-93A SK132693A3 (en) 1991-05-28 1992-05-15 Calcium, trace mineral, vitamin d and drug therapy combinations
CS932553A CZ281823B6 (cs) 1991-05-28 1992-05-15 Minerální a vitaminový doplněk pro výstavbu kostí
KR1019930703623A KR100244603B1 (ko) 1991-05-28 1992-05-15 칼슘,미량무기물,비타민 디 또는 디포스포네이트를 포함하는 골 강화용 식품 보충제
AU19968/92A AU666654B2 (en) 1991-05-28 1992-05-15 Calcium, trace mineral, vitamin D and drug therapy combinations
BR9206072A BR9206072A (pt) 1991-05-28 1992-05-15 Combinações de cálcio, traços de minerais, vitamina D e terapias com medicamentos.
JP5500425A JPH07502012A (ja) 1991-05-28 1992-05-15 カルシウム、微量ミネラル、ビタミンｄ及び薬物療法剤組合せ
NO934282A NO934282L (no) 1991-05-28 1993-11-26 Kalsium, spormetall, vitamin D og medisinterapikombinasjoner

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0600834A1 (fr) * 1992-11-30 1994-06-08 Ciba-Geigy Ag Utilisation de dérivés de l'acide méthanediphosphonique pour la fabrication d'un médicament pour le traitement de fractures
FR2704393A1 (fr) * 1993-04-30 1994-11-04 Boiron Complément nutritionnel absorbable pour optimiser la croissance et maintenir la solidité des os.
FR2723682A1 (fr) * 1994-08-19 1996-02-23 Boiron Complement nutritionnel absorbable pour l'equilibre quotidien de l'enfant et l'adolescent.
EP0702954A2 (fr) * 1994-09-26 1996-03-27 American Cyanamid Company Complément alimentaire à base de calcium
DE19503190A1 (de) * 1995-02-01 1996-08-08 Dietl Hans Mittel zur Beeinflussung von Störungen der Knochenbildung
US5597595A (en) * 1995-04-07 1997-01-28 Abbott Laboratories Low pH beverage fortified with calcium and vitamin D
US5609897A (en) * 1995-04-07 1997-03-11 Abbott Laboratories Powdered beverage concentrate or additive fortified with calcium and vitamin D
US5674844A (en) * 1991-03-11 1997-10-07 Creative Biomolecules, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US5698222A (en) * 1995-04-07 1997-12-16 Abbott Laboratories Calcium supplement
WO1998013062A1 (fr) * 1996-09-26 1998-04-02 Oklahoma Medical Research Foundation Utilisation de n-l-alpha-aspartyl-l-phenylalanine 1-methyl ester et de ses derives dans la regression de maladies
WO1998029123A1 (fr) * 1996-12-30 1998-07-09 Bone Care International, Inc. Procede de traitement de maladies prostatiques au moyen d'analogues actifs de la vitamine d
WO1998035674A1 (fr) * 1997-02-14 1998-08-20 Smith & Nephew Plc Compositions permettant d'inhiber la resorption osseuse
US5817351A (en) * 1995-04-07 1998-10-06 Abbott Laboratories Calcium fortified low pH beverage
WO2001003704A1 (fr) * 1999-07-08 2001-01-18 Wisconsin Alumni Research Foundation Calcium dietetique comme suplement des traitements de la sclerose en plaques a base de composes de vitamine d
US6255288B1 (en) 1992-11-30 2001-07-03 Novartis Corporation Certain methanebisphosphonic acid derivatives in fracture healing
US6503893B2 (en) 1996-12-30 2003-01-07 Bone Care International, Inc. Method of treating hyperproliferative diseases using active vitamin D analogues
US6566353B2 (en) 1996-12-30 2003-05-20 Bone Care International, Inc. Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US6573256B2 (en) 1996-12-30 2003-06-03 Bone Care International, Inc. Method of inhibiting angiogenesis using active vitamin D analogues
WO2005072539A1 (fr) * 2004-01-28 2005-08-11 Dr. Paul Lohmann Gmbh Kg Procede pour produire un compose de lactate-malate de calcium et compose de lactate-malate de calcium obtenu selon ledit procede
US6929797B2 (en) * 1997-02-13 2005-08-16 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
WO2006019843A1 (fr) * 2004-07-15 2006-02-23 Nanobac Life Sciences Procedes et compositions pour l'administration de chelateurs de calcium, de biphosphonates et/ou de composes de citrate et leurs utilisations pharmaceutiques
US7056882B2 (en) 1991-03-11 2006-06-06 Curis, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
WO2008020420A3 (fr) * 2006-08-17 2008-08-14 Procter & Gamble Compositions contenant du citrate-malate de calcium et leurs procédés d'obtention
WO2008020421A3 (fr) * 2006-08-17 2008-10-16 Procter & Gamble Composition de citrate-malate de calcium et son procédé d'élaboration
EP1993386A2 (fr) * 2006-02-21 2008-11-26 Nutrijoy Inc. Composition et procede de preparation de produits alimentaires et de boissons ayant une impression de gout ameliore contenant une proteine et des jus de fruits enrichis au point de vue nutritionnel par du calcium et des oligo-elements
WO2009019307A2 (fr) * 2007-08-09 2009-02-12 Novartis Ag Compositions à base de calcitonine orale et leurs applications
US8093228B2 (en) * 2005-09-16 2012-01-10 Selamine Limited Bisphosphonate formulation
US9867838B2 (en) 2009-09-01 2018-01-16 Duke University Methods for treating heart failure using bisphosphonate compositions
US9949992B2 (en) 2011-11-16 2018-04-24 Duke University Bisphosphonate compositions and methods for treating and\or reducing cardiac dysfunction

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2524610C (fr) * 2003-05-07 2014-03-25 Osteologix A/S Combinaisons a base de strontium pour la prophylaxie / le traitement d'affections touchant les cartilages et/ou les os
JP5619334B2 (ja) * 2006-06-14 2014-11-05 允聖 崔 骨強化剤

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992556A (en) * 1973-05-07 1976-11-16 Vitamins, Inc. Supplemented food product
GB2196523A (en) * 1986-09-12 1988-05-05 Beecham Group Plc Non-fat beverage
EP0300895A1 (fr) * 1987-07-23 1989-01-25 Nb International Technologies Mélange nutritif destiné à la personne âgée
JPH01218547A (ja) * 1988-02-26 1989-08-31 Snow Brand Milk Prod Co Ltd ビタミンｄ代謝産物を配合した育児用調製乳
EP0343703A2 (fr) * 1988-05-26 1989-11-29 The Procter & Gamble Company Suppléments minéraux avec alcool de sucre
WO1992002235A1 (fr) * 1990-08-06 1992-02-20 The Procter & Gamble Company Complements de calcium et de traces de mineraux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992556A (en) * 1973-05-07 1976-11-16 Vitamins, Inc. Supplemented food product
GB2196523A (en) * 1986-09-12 1988-05-05 Beecham Group Plc Non-fat beverage
EP0300895A1 (fr) * 1987-07-23 1989-01-25 Nb International Technologies Mélange nutritif destiné à la personne âgée
JPH01218547A (ja) * 1988-02-26 1989-08-31 Snow Brand Milk Prod Co Ltd ビタミンｄ代謝産物を配合した育児用調製乳
EP0343703A2 (fr) * 1988-05-26 1989-11-29 The Procter & Gamble Company Suppléments minéraux avec alcool de sucre
WO1992002235A1 (fr) * 1990-08-06 1992-02-20 The Procter & Gamble Company Complements de calcium et de traces de mineraux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J.E.F. REYNOLDS et al.: "Martindale the Extra Pharmacopoeia", 28th edition, 1982, pages 1657-1659, The Pharmaceutical Press, London, GB, see the whole document *
PATENT ABSTRACTS OF JAPAN vol. 13, no. 532 (C - 659) 28 November 1989 (1989-11-28) *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674844A (en) * 1991-03-11 1997-10-07 Creative Biomolecules, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US7056882B2 (en) 1991-03-11 2006-06-06 Curis, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US6255288B1 (en) 1992-11-30 2001-07-03 Novartis Corporation Certain methanebisphosphonic acid derivatives in fracture healing
EP0600834A1 (fr) * 1992-11-30 1994-06-08 Ciba-Geigy Ag Utilisation de dérivés de l'acide méthanediphosphonique pour la fabrication d'un médicament pour le traitement de fractures
FR2704393A1 (fr) * 1993-04-30 1994-11-04 Boiron Complément nutritionnel absorbable pour optimiser la croissance et maintenir la solidité des os.
US6537982B1 (en) 1993-09-10 2003-03-25 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues
FR2723682A1 (fr) * 1994-08-19 1996-02-23 Boiron Complement nutritionnel absorbable pour l'equilibre quotidien de l'enfant et l'adolescent.
EP0702954A2 (fr) * 1994-09-26 1996-03-27 American Cyanamid Company Complément alimentaire à base de calcium
KR960010009A (ko) * 1994-09-26 1996-04-20 이곤 이. 버그 개선된 칼슘 규정식 보충물
JPH08208490A (ja) * 1994-09-26 1996-08-13 American Cyanamid Co 改良されたカルシウム食事補助組成物
EP0702954A3 (fr) * 1994-09-26 1996-08-21 American Cyanamid Co Complément alimentaire à base de calcium
CN1117571C (zh) * 1994-09-26 2003-08-13 美国氰胺公司 改良的钙的饮食增补剂
DE19503190A1 (de) * 1995-02-01 1996-08-08 Dietl Hans Mittel zur Beeinflussung von Störungen der Knochenbildung
US5985335A (en) * 1995-02-01 1999-11-16 Orthomol Pharmazeutische Vertriebs Gmbh Agent for acting upon bone formation disturbances containing alkaline citrates, lactates and/or malates
WO1996023504A3 (fr) * 1995-02-01 1996-09-26 Orthomol Pharmazeutische Vertr Substance permettant d'agir sur les troubles de l'ossification, contenant des citrates, des lactates et/ou des malates alcalins
WO1996023504A2 (fr) * 1995-02-01 1996-08-08 Orthomol Pharmazeutische Vertriebs Gmbh Substance permettant d'agir sur les troubles de l'ossification, contenant des citrates, des lactates et/ou des malates alcalins
US5698222A (en) * 1995-04-07 1997-12-16 Abbott Laboratories Calcium supplement
US5609897A (en) * 1995-04-07 1997-03-11 Abbott Laboratories Powdered beverage concentrate or additive fortified with calcium and vitamin D
US5597595A (en) * 1995-04-07 1997-01-28 Abbott Laboratories Low pH beverage fortified with calcium and vitamin D
US5817351A (en) * 1995-04-07 1998-10-06 Abbott Laboratories Calcium fortified low pH beverage
WO1998013062A1 (fr) * 1996-09-26 1998-04-02 Oklahoma Medical Research Foundation Utilisation de n-l-alpha-aspartyl-l-phenylalanine 1-methyl ester et de ses derives dans la regression de maladies
US6177467B1 (en) 1996-09-26 2001-01-23 Oklahoma Medical Research Foundation Use of N-L-α-aspartyl-L-phenylalanine 1-methyl ester and its derivatives in disease regression
US6503893B2 (en) 1996-12-30 2003-01-07 Bone Care International, Inc. Method of treating hyperproliferative diseases using active vitamin D analogues
US6680309B2 (en) 1996-12-30 2004-01-20 Bone Care International, Inc. Method of treating hyperproliferative diseases using active vitamin D analogues
WO1998029123A1 (fr) * 1996-12-30 1998-07-09 Bone Care International, Inc. Procede de traitement de maladies prostatiques au moyen d'analogues actifs de la vitamine d
AU723835B2 (en) * 1996-12-30 2000-09-07 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues
US6566353B2 (en) 1996-12-30 2003-05-20 Bone Care International, Inc. Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US6573256B2 (en) 1996-12-30 2003-06-03 Bone Care International, Inc. Method of inhibiting angiogenesis using active vitamin D analogues
US6929797B2 (en) * 1997-02-13 2005-08-16 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
WO1998035674A1 (fr) * 1997-02-14 1998-08-20 Smith & Nephew Plc Compositions permettant d'inhiber la resorption osseuse
WO2001003704A1 (fr) * 1999-07-08 2001-01-18 Wisconsin Alumni Research Foundation Calcium dietetique comme suplement des traitements de la sclerose en plaques a base de composes de vitamine d
US6479474B2 (en) 1999-07-08 2002-11-12 Wisconsin Alumni Research Foundation Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis
WO2005072539A1 (fr) * 2004-01-28 2005-08-11 Dr. Paul Lohmann Gmbh Kg Procede pour produire un compose de lactate-malate de calcium et compose de lactate-malate de calcium obtenu selon ledit procede
WO2006019843A1 (fr) * 2004-07-15 2006-02-23 Nanobac Life Sciences Procedes et compositions pour l'administration de chelateurs de calcium, de biphosphonates et/ou de composes de citrate et leurs utilisations pharmaceutiques
US8093228B2 (en) * 2005-09-16 2012-01-10 Selamine Limited Bisphosphonate formulation
EP1993386A4 (fr) * 2006-02-21 2010-05-26 Nutrijoy Inc Composition et procede de preparation de produits alimentaires et de boissons ayant une impression de gout ameliore contenant une proteine et des jus de fruits enrichis au point de vue nutritionnel par du calcium et des oligo-elements
EP1993386A2 (fr) * 2006-02-21 2008-11-26 Nutrijoy Inc. Composition et procede de preparation de produits alimentaires et de boissons ayant une impression de gout ameliore contenant une proteine et des jus de fruits enrichis au point de vue nutritionnel par du calcium et des oligo-elements
WO2008020421A3 (fr) * 2006-08-17 2008-10-16 Procter & Gamble Composition de citrate-malate de calcium et son procédé d'élaboration
US7504536B2 (en) 2006-08-17 2009-03-17 The Procter & Gamble Company Compositions comprising calcium citrate malate and methods for making the same
AU2007285387B2 (en) * 2006-08-17 2010-06-24 The Procter & Gamble Company Compositions comprising calcium citrate malate and methods for making the same
AU2007285386B2 (en) * 2006-08-17 2011-02-03 The Procter & Gamble Company Compositions comprising calcium citrate malate and methods for making the same
CN101505731B (zh) * 2006-08-17 2011-11-16 宝洁公司 包含柠檬酸苹果酸钙的组合物以及它们的制备方法
WO2008020420A3 (fr) * 2006-08-17 2008-08-14 Procter & Gamble Compositions contenant du citrate-malate de calcium et leurs procédés d'obtention
US8889195B2 (en) 2006-08-17 2014-11-18 The Procter & Gamble Company Compositions comprising calcium citrate malate and methods for making the same
WO2009019307A3 (fr) * 2007-08-09 2009-09-24 Novartis Ag Compositions à base de calcitonine orale et leurs applications
WO2009019307A2 (fr) * 2007-08-09 2009-02-12 Novartis Ag Compositions à base de calcitonine orale et leurs applications
EP2460515A1 (fr) * 2007-08-09 2012-06-06 Novartis AG Compositions à base de calcitonine orale et leurs applications
US9867838B2 (en) 2009-09-01 2018-01-16 Duke University Methods for treating heart failure using bisphosphonate compositions
US9949992B2 (en) 2011-11-16 2018-04-24 Duke University Bisphosphonate compositions and methods for treating and\or reducing cardiac dysfunction

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JPH07502012A (ja) 1995-03-02
NO934282D0 (no) 1993-11-26
AU666654B2 (en) 1996-02-22
HU9303364D0 (en) 1994-03-28
CZ281823B6 (cs) 1997-02-12
AU1996892A (en) 1993-01-08
NZ242920A (en) 1995-06-27
BR9206072A (pt) 1994-11-15
CA2109958C (fr) 1997-06-10
NO934282L (no) 1994-01-28
HUT66379A (en) 1994-11-28
IE921701A1 (en) 1992-12-02
EP0586521A1 (fr) 1994-03-16
SK132693A3 (en) 1994-06-08
KR100244603B1 (ko) 2000-03-02
CZ255393A3 (en) 1994-07-13

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