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WO2004080210A1 - Compositions a base de metaux alimentaires destinees a soutenir le developpement physiologique des intestins et a prevenir la diarrhee - Google Patents

Compositions a base de metaux alimentaires destinees a soutenir le developpement physiologique des intestins et a prevenir la diarrhee Download PDF

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Publication number
WO2004080210A1
WO2004080210A1 PCT/EP2004/002437 EP2004002437W WO2004080210A1 WO 2004080210 A1 WO2004080210 A1 WO 2004080210A1 EP 2004002437 W EP2004002437 W EP 2004002437W WO 2004080210 A1 WO2004080210 A1 WO 2004080210A1
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Prior art keywords
zinc
dietary
acid
ppm
metal
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Ceased
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PCT/EP2004/002437
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English (en)
Inventor
Lisbeth Hoegh
Leif Hoejvang-Nielsen
Carsten Schmidt
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Boehringer Ingelheim Danmark AS
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Boehringer Ingelheim Danmark AS
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Publication of WO2004080210A1 publication Critical patent/WO2004080210A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/20—Inorganic substances, e.g. oligoelements
    • A23K20/30—Oligoelements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/30—Copper compounds
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to a novel concept of supporting the normal physiological development of the intestinal mucosa and/or preventing diarrhoea in animals, in particularly in pigs, chickens and calves, by increasing the local intraluminal bioavailability of dietary metal ions, such as zinc ions and copper ions, in the intestinal . tract of an animal.
  • the present invention further relates to pharmaceutical compositions formulated for controlled delivery of metal ions such as to prevent such dietary metal ions from being absorbed systemically from the stomach and duodenum, but to increase intraluminal concentrations of zinc ions and/or copper ions throughout the small intestinal tract of an animal.
  • a number of dietary metals such as zinc and copper, are reported as being of great importance for the proper growth and development of the digestive tract and for support of development of intestinal immune system of an animal.
  • supplemental administration of dietary metals is of importance to young animals where the small intestine is far from fully developed at the time of birth. After birth the small intestine still need to be developed such that proper conditions for effective uptake of nutrients is present.
  • the surface area of the small intestinal mucosa as determined by the number and length of intestinal villi should be as large as possible.
  • the absolute bioavailability of zinc oxide is estimated to be 10-20%.
  • the majority of the dietary intake of zinc oxide is not absorbed systemically, but recovered in the manure.
  • this induces a risk to the environment in that zinc salts may accumulate in cultivated soil via the use of manure as fertiliser.
  • organic sources of zinc may be more effective than inorganic sources due to higher bioavailability of zinc associated with an organic molecule, such as an amino acid. Accordingly, lower doses of zinc can be applied to feed. For example, by providing the dietary metal in complexed form with amino acid hydrolysates a higher systemic bioavailability of dietary metals in live stock animals was observed in comparison to zinc sulfate (US 5,698,724).
  • the present inventor has provided a novel concept of supplementing dietary metals to animals.
  • the concept aims at maximising intraluminal bioavailability of dietary metals in the small intestine of an animal, which may improve the likelihood of increasing the pool of dietary metals in intestinal mucosa cells.
  • the novel concept implies that lower doses of zinc may be supplemented to feed, such as doses equivalent to elemental zinc of at most 250 ppm in feed, while still being able of supporting proper intestinal development.
  • the present invention relates, at least in part, to novel compositions of dietary metals, such as zinc and copper, for minimised release of dietary metal ions in the gastric fluid, but for maximised release of dietary metals along the small intestine of an animal.
  • compositions with controlled release of dietary metals are contemplated.
  • Such compositions may, even in low doses, be effective in supporting the normal physiological development of the intestinal tract in an animal in need thereof and preventing the adverse effects of poor intestinal development such as diarrhoea in an animal.
  • compositions with controlled release of a dietary metal may upon per-orally administration to an animal result in high intraluminal concentrations of zinc throughout the small intestine.
  • a first aspect of the invention relates to a composition
  • a composition comprising dietary metals suitable formulated for per-oral administration and suitable formulated for limited release of said dietary metals in the stomach, said composition comprises; i) a source of dietary metal, wherein the metal is selected from the group consisting of zinc and copper; and ii) one or more acceptable excipient and or carrier, said composition releases less than 50 % of its content of said dietary metal when subjected to Dissolution Testing Method I for 0.5 hour, said Method I applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.4 04/2003 as the dissolution apparatus, 0.001 N HC1 as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • the release of said dietary metals from the composition is even more limited, such as less than 40%, more preferably less than 30%, such as less than 25%, 20%, 15%, 10% or 5% % of its content of said dietary metal is released when being subjected to said Dissolution Testing Method I.
  • composition may further be formulated so as to ensure the controlled release of dietary metals during the transit of the small intestinal tract.
  • a composition according to the invention may be formulated such that more than 30%, preferably more than 40%, such as more than 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95% of its content of said metal selected from the group consisting of zinc and copper is released when subjecting the composition to Dissolution Testing Method II for 1.0 hour, said Method II applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.4 04/2003 as the dissolution apparatus, 0.1 M phosphate buffer pH 7 as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • a second aspect of the invention relates to the use of the composition as mentioned herein as a feed/food additive or as a dietary supplement to animals.
  • the invention in a third aspect, relates to a method for supporting the physiological gastrointestinal development in an animal comprising administering to said animal an effective dose of a source of dietary metal, wherein the metal is selected from the group consisting of zinc and copper, said method further comprises that upon administering said effective dose of said source of dietary metal per-orally to said animal, less than 50% of the dose of said metal is recovered in the gastric juice during gastric residence time, and more than 50% of the dose of said metal is released into the small intestinal fluid during small intestinal transit time.
  • the invention relates to a method for preventing and treating diarrhoea in an animal comprising administering to said animal an effective dose of a source of zinc, such as ionised zinc, said method further comprises that upon administering said effective dose of said source of zinc to said animal, less than 50% of the dose of said metal is recovered in the gastric juice during gastric residence time, and more than 50% of the dose of said metal is released into the small intestinal fluid during small intestinal transit time.
  • a source of zinc such as ionised zinc
  • Another aspect of the invention relates to the use of a source of zinc for the preparation of a medicament for preventing and/or treating diarrhoea in an animal, said medicament releases less than 50 % of its content of said zinc when the medicament is subjected to Dissolution Testing Method I for 0.5 hour, said Method I applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.4 04/2003 as the dissolution apparatus, 0.001 N HCl as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • the present inventor has recognised the importance of providing sufficient local intraluminal available amounts of dietary metals, such as copper and zinc, throughout the small intestine of an animal. Furthermore, the present inventor has recognised that high . systemic bioavailability of dietary metals may not support normal physiological development of the small intestine of animal.
  • the present invention relates, at least in part, to limiting the systemic bioavailability of dietary metals and to provide sufficient concentrations of dietary metals in the intestinal fluid throughout the small intestine of an animal so as to increase the likelihood of providing high intracellular concentrations of zinc in small intestinal mucosa cells.
  • the present inventor put forth that upon targeting the release of dietary metals, such as zinc, in the small intestine of the gastrointestinal tract, the intracellular concentration of the metal binding protein, metallothionein, increases. This may in turn result in higher uptake of zinc into mucosa cells since metallothionein, an intracellular metal binding, maintains zinc homeostasis by controlling cellular zinc uptake, distribution and excretion. Thus, the pool of zinc in mucosa cells may increase, which is of great importance for cell proliferation of intestinal cells.
  • compositions for controlled release of dietary metals may be suitable formulated so as to limit high systemic bioavailability of zinc, for example by limiting the release of dietary metals in the gastric juice of the stomach.
  • compositions of the invention are formulated in a manner such that upon oral administration to an animal less than 50%, such as less than 40%, 30%, 25%, 20%, 15%, 10% or 5% of its content of dietary metal is recovered in the gastric juice during its gastric residence time.
  • less than 30%, preferably less than 25%, more preferably less than 20%, such as less than 15%, 10 5 or 5% of its content of dietary metal is recovered in the gastric juice during gastric residence time.
  • the controlled release of dietary metals include tlhe suitable formulation of the compositions of the inventions, such that upon oral administration to an animal more than 50%, such as more than 60%, 70%, 75%, 80%, 85%, 90% or 95% of its content of dietary metal is released in the small intestinal fluid during its small intestinal 10 transit time.
  • more than 75%, such as more than 80%, 85%, 90% or 95% of its content of dietary metal is released in the small intestinal fluid during its smaifl Intestinal transit time.
  • a first aspect of the invention relates to a composition intended for per- 15 oral administration comprising; i) a source of dietary metal, wherein the metal is selected from the group consisting of zinc and copper; and ii) one or more acceptable excipient and/or carrier, said composition is further characterised by releasing less than 50 %, preferably less than 20 40%, more preferably less than 30%, such as less than 25%, even more preferably less than
  • the present invention relates to controlled release of dietary metals for improving the local bioavailability of dietary metals in the small intestine of the gastrointestinal tract.
  • the compositions releases more than 20%, preferably more than 30%, such as more than 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95% of its content of said dietary metal when being subjected to Dissolution Testing Method II for 1.0 hour, said Method II applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.4 04/2003 as the dissolution apparatus, 0.1 M phosphate buffer pH 7 as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • more than 20%, preferably more than 30%, such as more than 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95% of its content of said dietary metal is released when subjecting the composition to said Dissolution Testing Method II for 0,5 hour.
  • the term "dietary metal” encompasses metals that form part of normal dietary requirements for mammals, such as animals and humans including zinc, copper, cobalt, manganese and iron.
  • the dietary metal is copper and/or zinc.
  • the dietary metal is zinc, which has a beneficial effect in preventing diarrhoea in animals, such as in animals with poor developed small intestine.
  • the term "ionised form” encompasses various oxidation states of a dietary metal, such as a monovalent, a divalent or a trivalent kation of a dietary metal, e.g, a kation selected from the group of elemental dietary metals consisting of Zn + , Zn 2+ , Cu + , Cu 2+ , Mn + , Mn 2+ , Fe2 + , Fe 3+ .
  • the term “ionised form” is denoted to include kations of dietary metals in oxidation states that are normally present in the gastro-intestinal tract, such as Zn 2+ , Cu 2+ and Fe 3+ .
  • a dose equivalent to elemental zinc is denoted to mean the dose of elemental zinc in a source of zinc.
  • acceptable carriers and excipients is intended to mean substances, which are substantially harmless to the individual to which the composition will be administered. Such excipients normally fulfil the requirements given by national drug agencies and/or feed stuff legislation, Official pharmacopeias such as the United States of America Pharmacopeia and the European Pharmacopeia set standards for well-known pharmaceutically acceptable excipients.
  • oral administration is intended to mean administration to an individual of a composition trough the mouth, preferably where the release and absorption of the therapeutically active principle is not intended to occur in the oral cavity, but rather after passing the oral cavity, such as in the gastro-intestinal tract.
  • an animal characterises an animal, including a human, in need of supplementary doses of dietary metals, such as zinc and copper.
  • the animal may further be characterised by having or being prone to poor development of the small intestine. Signs on poor development of the small intestine include presence of adverse changes in intestinal morphology, including reduced villus height (villus atrophy), increased villus width with oedema, increased crypt dept and reduced absorptive capacity and brush border enzyme activity.
  • the animal may also be characterised by being in growth phase, such as a young animal before being fully matured as an adult animal.
  • Presently interesting examples of animals include pigs, in particularly weaned pigs, pigs in growth phase; chickens such as chickens in growth phase; and calves such as calves in growth phase.
  • controlled release is denoted to mean any release of dietary metals from a composition, including the metal on ionised form, in complexed form or any other suitable form, wherein the release rate is modified in a controlled, retarded, sustained, delayed and/or in any other manner in comparison to the release of dietary metals from a composition consisting of animal feed products.
  • controlled release may in its broadest sense relate to the release of dietary metals from a composition such that a) when subjecting the composition to Dissolution Testing Method I for 0.5 hour, less than
  • said Method I applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.404/2003 as the dissolution apparatus, 0.001 N HCl as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed, and/or b) when subjecting the composition to Dissolution Testing Method ⁇ for 1.0 hour more than 20% of its content of said dietary metal is released, said Method II applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.404/2003 as the dissolution apparatus, 0.1 M phosphate buffer pH 7 as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • small intestine is denoted to include duodenum, proximale jejunum, middle jejunum, distale jejunum and ileum.
  • the term "small intestine” or the phrase “intestinal part of the gastro-intestinal tract” is denoted to include proximale jejunum, middle jejunum, distale jejunum and ileum, preferably to include middle jejunum, distale jejunum and ileum.
  • systemic bioavailability is in generally terms denoted to mean the percentage of a dose of dietary metals absorbed into the circulating blood upon administering a single dose or after administering several doses such as at steady state conditions.
  • the systemic bioavailability may be determined on the basis of plasma AUC.
  • dietary metals may only shortly be present in the circulating blood after absorption due to high distribution into other tissues. Therefore, systemic bioavailability may be determined by measuring the recovered amount of dietary metals in storage tissues such as liver, kidney, bones and/or excretion in urine or combinations thereof.
  • intraluminal bioavailability or "local bioavailability” is intended to denote the percentage of a dose of dietary metals released into the small intestine of an animal.
  • the uptake of dietary metals in small intestinal mucosa cells may be a measure of "intraluminal bioavailability” or "local bioavailability”.
  • compositions of the invention comprise a source of a dietary metal.
  • source of a dietary metal is denoted to niean substances with content of dietary metal, preferably zinc and/or copper, wherein the dietary metal may be in various oxidation stages in the form of a salt or a chelate.
  • interesting sources of dietary metal relates to those easily soluble in water.
  • the source of dietary metal according to the invention may be characterised by having a solubility of at least 0.02 mg/ml, preferably at least 0.05 mg/ml, more preferably at least 0.1 mg/ml, still more preferably at least 0,5 mg/ml, most preferably at least 0,7 mg/ml, such as at least 1 mg/ml, 2 mg/ml, 3 mg/ml and 4 mg/ml. when subjected to water at 25 °C.
  • the source of dietary metal is a metal salt, such as a zinc salt and/or a copper salt, of an inorganic acid, wherein the inorganic acid is selected from the group consisting of hydrobromic acid, hydrochloric acid, hydroiodic acid, nitric acid and sulfuric acid.
  • the salt is a zinc salt and/or copper salt of an inorganic acid, such as zinc bromide, zinc chloride, zinc iodide, zinc nitrate, zinc sulfate, copper bromide, copper chloride, copper iodide, copper nitrate or copper sulfate.
  • the source of a dietary metal is a dietary metal salt, such as a zinc salt and/or a copper salt, of an organic acid, wherein the organic acid is selected from the group consisting of acetic acid, citric acid, formic acid, lactic acid, glucoronic acid, oxalic acid and propionic acid.
  • interesting zinc salts of organic acids relate to zinc acetate, zinc citrate, zinc lactate, zinc gluconate, zinc oxalate, zinc propionate, copper acetate, copper citrate, copper lactate, copper gluconate, copper oxalate or copper propionate.
  • the zinc salt is zinc sulfate, zinc chloride, zinc acetate or hydrates thereof and the copper sulfate, copper chloride, copper acetate or hydrates thereof.
  • chelates of dietary metals with amino acids and polysaccharides may be of great importance for achieving high systemic bioavailability.
  • the use of such chelates may not be anticipated as long as such chelates are prevented from being absorbed in the proximal parts of the gastro-intestinal tract, such as the stomach and duodenum.
  • the dietary metals is complexed to a ligand, wherein said ligand is selected from the group consisting of saccharides, amino acids, di- carboxylic acids, and ⁇ -hydroxy acids and/or EDTA.
  • ligand is selected from the group consisting of saccharides, amino acids, di- carboxylic acids, and ⁇ -hydroxy acids and/or EDTA.
  • interesting complexes of dietary metals include complexes with ascorbate, aspartate, citrate, histidine, malate, maltol, gluconate, glutamate, succinate, tartrate, lysine or methionine.
  • compositions of the invention may include mixtures of one or more dietary supplements, such as for example sources of zinc in combination with sources of copper or other dietary metals.
  • the source of dietary metal is a source of zinc, such as ionised zinc
  • the source of zinc is in an amount equivalent to elemental zinc in the range of 2% to 50% w/w, such as 2-30%, such as 25-25% w/w.
  • the composition is added to feed.
  • said source of zinc such as a source of ionised zinc
  • said source of zinc in an amount equivalent to elemental zinc in the range from about 25 to 1000 ppm in feed, such as from about 50 to 500 ppm, 50 to 400 ppm, 50 to 300 ppm, preferably from about 50 to 250 ppm, more preferably from about 100 to 250 ppm in feed.
  • compositions may be suitable formulated so as to limit the absorption of dietary metals from the upper part of the gastro-intestinal tract, such as the stomach and/or the duodenum or a part of duodenum, and to release the dietary metals throughout, or at least to the main part of, the small intestine of an animal. It is however not anticipated that the release of dietary metals may continue during the transit of large bowel.
  • the composition further comprises a release-rate controlling agent.
  • a release-rate controlling agent may be selected from the group consisting of waxes, fats, proteins, polymeric organic compounds, such as celluloses and polysaccharides, and combinations thereof.
  • the release-rate controlling agent include ethyl cellulose, which may be provided as an outer coating or in an core or combinations thereof.
  • compositions of the invention may be formulated in a number of manners as long as the per-oral administration of the composition results in minimised release of dietary metal ions in the gastric fluid, as indicated by a limited systemic bioavailability, and maximised release of dietary metal ions in the small intestinal fluid, preferably such that dietary metal ions is continuously released throughout the intestinal tract, preferable the small intestinal tract.
  • the compositions are formulated as solids.
  • such embodiments have a moisture content of less than 50%, such as less than 40%, 30%, 25%, 20%, 15%, 10% and 5%.
  • other forms of the composition such as semi-solids or liquids are not anticipated.
  • compositions of the invention may be provided as crystals, granules, pellets, spheres, beads, matrixes or other types of agglomerates that allow for oral administration to an animal.
  • the compositions is pre- mixed with feeds and/or nutrients or incorporated into feed substances or nutrients, for example animal feed or feed substances such as fibers approved according to Feeding Stuffs Regulations.
  • the composition of the invention may be added to feed, such as provided as top dressing.
  • said granules, pellets, spheres, beads, matrixes or other types of agglomerates are essentially spherical.
  • compositions of the invention may further be characterised by including one or more core(s), wherein the source of dietary metal may be incorporated or not.
  • cores as well as compositions of the invention in general may comprise one or more of acceptable ca riers and excipients such as diluents, binders, disintegrants, wetting agents, lubricants, glidants, flow aids and/or flavours.
  • the core may comprise a polysaccharide such as chitosan.
  • core is denoted to mean a matrix formed by dry, melt or wet granulation or by blending of acceptable excipients.
  • diluents include lactoses, starches, mannitol, sorbitol, xylitol, dextroses, phosphates, sucroses, calcium sulfates, calcium lactates, dextrates, inositol, celluloses, calcium carbonates, glycine, bentonite, polyethylenglycol, polyvinylpyrrolidone or mixtures thereof.
  • binders include acacia, tragacanth, sucrose, gelatin, glucose, starches, pregelatinized starches, celluloses including methylcellulose and sodium carboxymethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, polyethylenglycol, guar gum, polysaccharides, bentonites, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose or mixtures thereof.
  • disintegrants examples include starches, clays, celluloses, croscarmellose sodium, alginates, crospovidone, gums or mixtures thereof.
  • wetting agents include quaternary ammonium compounds, phenyl ethers, polyoxyethylene fatty acid/sterates/glycerides and oils, sorbitan esters, propylene glycol fatty acid esters, glyceryl fatty acid esters.
  • Typical examples of lubricants, glidants or flow aids include glyceryl behapate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates, hydrogenated vegetable oils, colloidal silica, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycols, sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate, and stabilisers such as desiccating amorphous silica or mixtures thereof. Suitable flavours are those typically used by a person skilled in the art.
  • the core essentially consists of a diluent selected from the group consisting of lactose, starches, sugars, polysaccharides metal salts, celluloses, minerals and polymers.
  • the core is in the form of a sugar sphere.
  • the core is made of excipients that may not substantially affect the release rate of the dietary metal ions such as for example easily soluble excipients such as sucrose.
  • the core comprises one or more agents that may control the release rate of dietary metal ions, such as chitosan.
  • the core may be coated with a release-rate controlling agent.
  • the minimised release of dietary metal ions in gastric fluid and the maximised release of dietary metal ions in the intestinal tract of an animal is provided, at least in part, by incorporating one or more release-rate controlling agent(s) in the composition.
  • Typical principles of incorporating a release-rate controlling agent in a composition of the invention include:
  • the source of a dietary metal in an core, wherein the core is coated with an outer coating comprising one or more release-rate controlling agent(s).
  • the source of a dietary metal is mixed with one or more suitable excipients so as to incorporate the source of a dietary metal in one or more cores, and coating the resulting core(s) with an outer coating comprising a release-rate controlling agent.
  • the release of metal ions from the composition may in addition be controlled by incorporating one or more release-rate controlling agent(s) in the core.
  • cores or matrixes made of one or more excipients wherein the source of a dietary metal is applied onto the surface of said cores or matrices in mono or multiple layers and coating the resulting cores with an outer coating comprising a release-rate controlling agent.
  • said core may comprise a release-rate controlling agent.
  • release-rate controlling agent is denoted to characterise an agent, which
  • Typical pH-dependent rate limiting barriers relates to agents, which is substantially insoluble in gastric juices, e.g. pH below 4, thus preventing release of dietary metal ions in gastric fluid.
  • agents in order to release dietary metal ions in the intestinal tract, such agents should dissolve or otherwise be removed upon being contacted with the intestinal fluids.
  • enteric coatings which is denoted to mean any pharmaceutically acceptable agent that has a low solubility or is practically insoluble at low pH, such as below pH 4, but may dissolve at higher pH values, such as from pH 4 to 7.5, more preferably from pH 6 to 7.5, or may be destroyed by enzymatically processes.
  • an enteric coating is provided by agents that remains intact for at least 60 minutes, preferably at least 80 minutes, more preferably at least 100 minutes when being contacted with artificial gastric juices such as HCl of pH 3 at 37°C or 39°C.
  • suitable agents should dissolve or disintegrates upon being contacted with artificial intestinal juices such as a KH 2 PO 4 buffered solution of pH 6.8 or higher such as 7 or 7.5 within the first 30 minutes of contact.
  • the most effective enteric polymers are polyacids having a pKa of 3 to 5.
  • enteric coatings include pH-sensitive enteric polymers, preferably those that dissolves at pH levels above pH levels of the gastric fluid such as pH above 4, 4.5, 5, 5.5, 6, 6.5, 7.0 or pH 7.5 and include
  • Typical examples of cellulose acetate phthalates have an acetyl content of 17-26% and phthalate content of from 30-40%.
  • An example of an appropriate cellulose acetate phthalate is the marketed product CAP®.
  • Typical examples of cellulose acetate trimellitates have an acetyl content of 17-26%, a trimellityl content from 25-35%.
  • An example of an appropriate cellulose acetate trimellitate is the marketed product CAT®.
  • HPMCP Hydroxypropyl methylcellulose phthalate
  • Hydroxypropyl methylcellulose phthalates typically have a molecular weight of from 20,000 to 100,000 daltons, e.g. a hydroxypropyl content of from 5 to 10%, a methoxy content of from 18 to 24% and a phthalyl content from 21 to 35%.
  • Methylacrylates include those of molecular weight above 100,000 daltons based on, e.g. methylacrylate and methyl or ethyl methylacrylate in a ratio of about 1:1.
  • Typical products include Endragit L, e.g.
  • Eudragit® L 100-55 spray dried Eudragit ® L 30 D-55 which can be reconstituted for aqueous formulations for targeted drug delivery in the duodenum; Eudragit ® L 30 D-55 pH dependent anionic polymer solubilizing above pH 5.5; Eudragit ® L 100 pH dependent anionic polymer solubilizing above pH 6.0 and Eudragit ® S 100 pH dependent anionic polymer solubilizing above pH 7.0.
  • HPMCAS Hydroxypropyl methylcellulose acetate succinate
  • Hydroxypropyl methylcellulose acetate succinate include polymers in aqueous preparations such as Aqoat®.
  • Polyvinyl acetate phthalate include, aqueous coating formulation of the polymers such as Opadry-entric®, Surelease® and Sureteric®.
  • CMEC Carboxy methyl ethyl cellulose
  • the enteric coating are made from cellulose acetate phthalate and trimellitate, methacrylic acid copolymers e.g. copolymers derived from methylacrylic acid and esters thereof, hydroxypropyl methylcellulose phthalate, and polyvinyl acetate phthalate.
  • the enteric coating may be applied using conventional techniques implying that the cores or compositions are sprayed with an aqueous or non-aqueous coating suspension or solution of the enteric-coating to form a film coating. In general, satisfactory results are obtained with a coating of 5-100 ⁇ m, preferably 20-80 ⁇ m thickness.
  • Suitable solvents for dissolving or suspending the enteric-coating include organic solvents, e.g. alcohols such as methanol, ethanol and isopropanol, a ketone such as acetone, halogenated hydrocarbons such as methylenchloride or mixtures of such solvents. Other suitable solvents are mixtures of the above mentioned solvents and water.
  • the enteric coating may also be used together with a plasticizer, such as esters of citric acid, tartaric acid and succinic acid; glycerol and glycerol esters; phthalic acid esters; glycols such as ethylene glycols, propylene glycols, polyethylene glycols and esters thereof; adipates; benzophenone; polysorbates ; or sorbitan monooleate.
  • a plasticizer such as esters of citric acid, tartaric acid and succinic acid; glycerol and glycerol esters; phthalic acid esters; glycols such as ethylene glycols, propylene glycols, polyethylene glycols and esters thereof; adipates; benzophenone; polysorbates ; or sorbitan monooleate.
  • the enteric coating may also include an anti-tack agent such as talc, silica or glyceryl monostearate.
  • an anti-tack agent such as talc, silica or glyceryl monostearate.
  • the quantity of plasticizer and anti-tack agent may be generally conventional to the art.
  • the coating may include about 10-25 wt % of plasticizer and up to about 50 wt % of anti tack agent, e.g. 5-20 wt % of anti-tack agent.
  • interesting release-rate controlling agents of the invention relates to those agents that controls the release of dietary metal through simple diffusion, independent of the pH in the surrounding environment, in that the fluid may be able to slowly diffuse into coatings or cores comprising such agents, which in turn may dissolve the dietary metals upon where the metals escapes from the composition by diffusion through the coating membrane or out of the core.
  • an agent that controls the release rate by diffusion is denoted to mean agents that may form coatings that are fully permeable to fluids such as water and any substance dissolved herein.
  • Typical interesting agents relates to film-forming polymeric substances characterised by being substantially water- insoluble, but water-diffusible and substantially pH-independent, or the agent may be a hydrophobic agent:
  • Typical examples of film-forming polymeric substances contemplated for the purpose of the present invention are cellulose derivatives, for instance ethylcellulose, acrylic polymers, vinyl polymers, and other high molecular synthetic polymers such as ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate, polyvinyl acetate, polyvinyl formal, polyvinyl butyral, polymethyl methacrylate, polycarbonate, polystyrene, polyester, coumaroneindene polymer, polybutadiene, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate copolymer and vinyl chloride-propylene-vinyl acetate copolymer.
  • cellulose derivatives for instance ethylcellulose, acrylic polymers, vinyl polymers, and other high molecular synthetic polymers
  • ethylcellulose cellulose acetate, cellulose propionate, cellulose
  • the film-forming polymer is ethylcellulose.
  • hydrophobic substances are waxes or wax-like substances.
  • wax-like substances are carnauba wax, beeswax, paraffin wax, ceresine, shellac wax, castor wax, and higher fatty acids such as myristic, palmitic, stearic and behenic acids and esters thereof.
  • the above-mentioned film-forming and/or hydrophobic substance is mixed with an acceptable water-soluble substance so as to modify the desired diffusion properties of the film, e.g. so as to achieve continuous release of dietary metal ions from the composition.
  • Typical examples of such acceptable water-soluble substance are selected from polyethylenglycol, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose and polyvinylpyrrolidone and other water-soluble polymers known by a person skilled in the art.
  • suitable embodiments of the invention relate to those wherein the source of a dietary metal is incorporated into a core.
  • a sub-coat consequently lies beneath the coat of a release-rate controlling agent.
  • Suitable sub-coat materials include hydroxypropylmethyl cellulose.
  • the over-coat may be of the same material as the sub-coat. Typically such coatings may be applied by known techniques of aqueous film coating.
  • the release-rate controlling agent is preferably controlling the release rate by diffusion of erosion or combinations thereof.
  • release-rate controlling agent is meant to include without restriction polymers, such as ethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyethylenglycol, methacrylates, polymethylmethacrylate, carbomer, alginates and xanthan gums.
  • the release-rate controlling agent is meant to include hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, protein derived materials, nylon, acrylic resins, polylactic acid, polysaccharides such as starches, cellulose acetate phthalate.
  • hydrophilic or hydrophobic polymers such as gums, cellulose ethers, protein derived materials, nylon, acrylic resins, polylactic acid, polysaccharides such as starches, cellulose acetate phthalate.
  • cellulose ethers especially substituted cellulose ethers such as alkylcelluloses, in particularly ethylcellulose, d. -C 6 hydroxyalkylcelluloses (such as hydroxypropylcellulose and especially hydroxyethyl cellulose) and acrylic resins (for example methacrylates such as methacrylic acid copolymers) and polysaccharides (such as Chitosan) are preferred.
  • the release-rate controlling agent is meant to include digestible, long chain (C 8 -C 50 , especially C 8 - o), substituted or unsubstituted hydrocarbons, such as fatty acids, hydrogenated vegetable oils, hardened rapeseed oil, castor oil, coconut oil, beef tallow, palm oil, palm kernel oil and soya bean oil, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), glyceryl esters of fatty acids for example glyceryl esters of fatty acids for example glyceryl monostearate, monoacyl and diacylglycerols esterified with acetic-, lactic-, citric-, tartaric-, monoacetyltartaric- and/or diacetyltartaricacid, mineral oils and waxes, e.
  • C 8 -C 50 especially C 8 - o
  • the core comprises a polysaccharide such as chitosan.
  • chitosan encompasses a series of chitosan polymers with different molecular weights and degree of acetylation.
  • the release rate of dietary metal ions from the chitosan core is determined, at least in part, by the degree of swelling of the chitosan in that the release rate may become constantly and continuos when the degree of swelling has reached its equilibrium state.
  • the core or matrix may conveniently comprise between 1 wt % and 99 wt % of said hydrophilic or hydrophobic polymer.
  • the composition is formulated a semisolid preparation, such as a paste, gel, cream or ointment, wherein the release of the dietary metal ions is targeted to the intestinal tract.
  • a semisolid preparation such as a paste, gel, cream or ointment, wherein the release of the dietary metal ions is targeted to the intestinal tract.
  • the semisolid preparations can be prepared by techniques known by the person skilled in the art.
  • the composition is formulated as liquid preparations.
  • Preferred liquid preparations include suspension and emulsion, wherein the release of dietary metal ions is targeted to the intestinal tract.
  • the suspensions and emulsions can be prepared by techniques known by the person skilled in the art.
  • compositions may comprise a release-rate controlling agent for controlled release.
  • a release-rate controlling agent for controlled release.
  • the in vitro release of dietary metals from the composition when being subjected to said Dissolution Testing Method II as described herein is as follows:
  • ⁇ more than 50%, preferably more than 60%, such as more than 70%, 75%, 80%, 85%, 90% or 95% of the content of said dietary metal is released following in vitro testing for 4.0 hours.
  • 60-80% preferably 60-80% such as 60-90% or 60-100% of the content of said dietary metal is released following in vitro testing for 2.0 hours.
  • the in vitro release of dietary metals from a composition may be investigated at pH 6.5 and 7.0, in particularly when aiming at simulating the pH values in the middle and distale part of the small intestine of an animal.
  • said Dissolution Testing Method II may be applied with alternative pH values such as pH 6.5 and pH 7.0.
  • compositions of the invention mainly relates to supplementing live stock animals, in particularly animals in growth phase, with dietary metals, in particularly copper and zinc, for supporting and improving the normal proliferation of intestinal cells, thus enhancing the absorptive area of the small intestine.
  • dietary metals in particularly copper and zinc
  • the animal may suffer from diarrhoea, anorexia, villus atrophy, poor growth, improved susceptibility to infectious bacteria and poor recovery from virus diarrhoea.
  • a second aspect of the invention relates to the use of compositions of the invention as a feed/food additive or as a dietary supplement to animals, e.g for supporting the physiological gastro-intestinal development and in the event where the composition comprises zinc, the feed/food additive or dietary supplement may be used in the prevention of diarrhoea in an animal. Also the use of the feed/food additive or dietary supplement for supporting the recovery from virus diarrhoea is anticipated.
  • a further aspect of the invention relates to a method of supporting the physiological gastro-intestinal development in an animal, comprising administering to said animal an effective dose of a source of a dietary metal, preferably zinc and/or copper, wherein said method further comprises that upon administering said effective dose of said source of dietary metal per-orally to said animal, less than 50% of the dose of said metal is recovered in the gastric juice during gastric residence time, and more than 50% of the dose of said metal is released into the intestinal fluid during small intestinal transit time.
  • a still further aspect of the invention relates treating and/or preventing of diarrhoea in an animal, wherein a source of zinc is provided in a form that limits the absorption from the duodenum and proximal part of the jejunum and maximises the local bioavailability of zinc throughout the small intestinal tract.
  • the invention relates to a method of preventing and treating diarrhoea in an animal comprising administering to said animal an effective dose of a source of zinc, said method further comprises that upon administering said effective dose of said source of zinc per-orally to said animal, less than 50% of the dose of said metal is recovered in the gastric juice during gastric residence time, and more than 50% of the dose of said metal is released into the small intestinal fluid during small intestinal transit time. 5
  • the methods imply that less than 40%, preferably less than 30%, more preferably less than 25%, such as less than 20%, 10 15%, less than 10% or less than 5% of the dose of said metal is recovered in the gastric juice during gastric residence time.
  • more than 60%, preferably more than 70%, more preferably more than 75%, such as more than 80%, more than 85%, more than 90% or more than 95% of the dose of said metal is released into the small intestinal fluid during small intestinal transit time.
  • the method of preventing and treating diarrhoea in an animal comprises administering said source of zinc for the first 10 weeks after weaning, preferably for the first 9 weeks, such as 8 weeks, 7, 6, 5, 4, 3 weeks or 2 weeks after weaning.
  • the invention relates to the use of a source of zinc for the preparation of a medicament for preventing and/or treating diarrhoea in an animal, said medicament releases less than 50 % of its content of zinc when the medicament is subjected to Dissolution Testing Method I for 0.5 hour, 25 said Method I applies to a Basket Apparatus according to the European Pharmacopoeia Supplement 4.4 04/2003 as the dissolution apparatus, 0.001 N HCl as the dissolution medium, 39°C as the temperature and 100 rpm as the rotation speed.
  • the diarrhoea as referred to herein include diarrhoea related to animals in growth phase; 0 weaning diarrhoea; neonatal coli diarrhoea (for example caused by E. coli); proliferative enteropathy (for example caused by Lawsonia intracellularis). Furthermore, generally speaken, the diarrhoea relates to diarrhoea of animals with poor development of the intestinal tract as defined by presence of villus atrophy. In further embodiments, wherein the animal is a pig, the diarrhoea is Swine dysentery that may be caused by Serpulina hyodysenteriae.
  • animals infected with bacteria capable of provoking diarrhoea such as E. coli, Lawsonia intracellularis, Serpulina hyodysenteriae, may be subject to the uses and methods as described herein.
  • said methods and uses as described herein further comprises that the source of a dietary metal or a source of zinc may be provided in the form of a composition of the present invention, as described supra.
  • the methods and uses described herein include the administration to an animal.
  • the uses and methods include an animal selected from the group consisting of pigs, calves and chickens.
  • uses and methods as described herein relates to weaned pigs or pigs in the period of weaning.
  • the source of zinc may be supplemented to the animal in admixture with feed such that the dose equivalent to elemental zinc in feed is from about 25 to 1000 ppm, such as from about 50 to 500 ppm, 50 to 400 ppm, 50 to 300 ppm, preferably from about 50 to 250 ppm, more preferably from about 100 to 250 ppm.
  • compositions of the invention comprises the following ingredients:
  • Zinc Zinc sulphate mono hydrate; zinc chloride, zinc acetate, zinc sulphate hepta hydrate, zinc lactate dihydrate or zinc lactate trihydrate); and 25-80% Ethyl cellulose; and/or 25-80% ethyl cellulose and chitosan; and/or 25-80% Acetic acid ester of monoglycerides from vegetable oil; and/or 25-80% Vegetable oil; and/or 25-80% Vegetable hydrogenated oil; and/or 5-10% Amylopectin, pregelatinized or not pregelatinized;
  • Free flow auxiliary e.g Silicium dioxide
  • compositions of the invention include:
  • composition essentially consisting of an inner core of sugar sphere coated with a first layer of zinc sulphate and thereafter coated with one or more layer of ethyl cellulose and finally coated with a layer of sucrose, either sprayed on or as a powder.
  • composition essentially consisting of an inner core of sugar sphere coated with a first layer of zinc sulphate and thereafter one layer of chitosan (deacetylised) and thereafter one or more layers of ethyl cellulose and finally coated with a layer of sucrose, either sprayed on or as a powder.
  • composition essentially consisting of a mixture of zinc sulphate and a vegetable fat (hydrogenated or not), which is spray cooled into solid particles.
  • a vegetable fat hydrophilic or not
  • ethyl cellulose ethyl cellulose
  • chitosan deacetylated
  • a composition essentially consisting of zinc sulphate and an acetic acid ester of a monoglyceride from a vegetable oil sprayed in a spray cooler into particles.
  • chitosan deacetylated
  • composition essentially consisting of pelletised or extruded zinc sulphate and chitosan micro particles coated with one or more outer layers of ethyl cellulose in a rotation drum.
  • composition essentially consisting of zinc sulphate coated with one or more layers of ethyl cellulose in a fluid bed.
  • compositions optionally further comprise binders or fats/oils or starch as pre-conditioners and are optionally covered with sugar film or sugar powder.
  • a composition according to the present invention comprising an amount of Zn equivalent to 250 ppm of Zn element ii) Zinc sulphate monohydrate in an amount equivalent to 250 ppm of Zn element (easy soluble zinc salt) iii) ZnO in an amount equivalent to 3000 ppm of Zn element
  • Piglets from each trial group are investigated as follows: At day 14 after weaning a number of piglets from each group are euthanasized and an autopsy is performed. Samples of mucosal intestinal tissue are taken from different compartments of the small intestinal canal, the duodenum, the jejunum and the ileum and immediately preserved for the purpose of determination of the intracellular content of both metallothionein (MT) and Zinc.
  • MT metallothionein
  • Intestinal metallothionein is determined by a Cadmium saturation assay.
  • the invention By measuring the induction of intracellular Zn in enterocytes of different compartments of the small intestine it is shown that the invention induces high intracellular concentration of Zn which can support proliferation and differentiation of enterocytes in the different compartments of the small intestinal canal.
  • Zinc content of the different intestinal segments is determined by a spectrophotometrical analysis.
  • a number of piglets from each group are euthanasized and an autopsy is performed. Samples of intestinal tissue are taken from different compartments of the small intestinal canal, the duodenum, the jejunum and the ileum and preserved for histological examination and determination of villus height and crypt depth.

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Abstract

Nouveau concept destiné à soutenir le développement physiologique normal de la muqueuse intestinale et / ou à prévenir la diarrhée chez les animaux, en particulier chez les porcs, les poulets et les veaux, reposant sur l'augmentation de la biodisponibilité intraluminale locale d'ions métalliques alimentaires, tels que des ions de zinc et des ions de cuivre, dans le tractus intestinal d'un animal.
PCT/EP2004/002437 2003-03-14 2004-03-10 Compositions a base de metaux alimentaires destinees a soutenir le developpement physiologique des intestins et a prevenir la diarrhee Ceased WO2004080210A1 (fr)

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EA017656B1 (ru) * 2007-11-22 2013-02-28 Фарматека Дьярто Эш Керешкедельми Бт Композиция для профилактики и лечения дизентерии свиней
WO2009066117A1 (fr) 2007-11-22 2009-05-28 Pharmateka Kiskereskedelmi Bt Utilisation de l'edta et de ses dérivés pour la prévention et le traitement de maladies intestinales bactériennes des porcs et pour l'augmentation des effets d'antibiotiques exercés dans de telles maladies
ITMI20111555A1 (it) * 2011-08-29 2013-03-01 Cevolani Daniele S R L Mangimi e composizioni per uso veterinario e/o zootecnico
AU2017203095B2 (en) * 2012-06-29 2018-11-22 Dr. Bata Zrt. Antibacterial microelement chelates and the use thereof in animal feeds
WO2014001924A1 (fr) 2012-06-29 2014-01-03 Dr. Bata Zrt. Chélates de microéléments antibactériens et utilisation associée dans des nourritures animales
JP2015524388A (ja) * 2012-06-29 2015-08-24 ディーアール．バータ ゼットアールティー．ＤＲ．ＢＡＴＡ ＺＲｔ． 抗菌微量元素キレート及び動物飼料での使用
US10821093B2 (en) 2012-06-29 2020-11-03 Dr. Bata Zrt. Antibacterial microelement chelates and the use thereof in animal feeds
US10022350B2 (en) 2012-06-29 2018-07-17 Dr. Bata Zrt. Antibacterial microelement chelates and the use thereof in animal feeds
WO2014033490A1 (fr) 2012-08-30 2014-03-06 PHARMATÉKA Kutató, Fejlesztö és Szolgátató Kft. Produits de prévention contre des germes pathogènes, et leur procédé d'utilisation
CN106262617B (zh) * 2016-08-23 2020-03-31 内蒙古阜丰生物科技有限公司 包含黄原胶的食品添加剂的制备工艺
CN106262617A (zh) * 2016-08-23 2017-01-04 内蒙古阜丰生物科技有限公司 包含黄原胶的食品添加剂的制备工艺
WO2018084805A1 (fr) * 2016-11-01 2018-05-11 Xylonix Ip Holdings Pte. Ltd. Compositions d'acide gamma-polyglutamique et de zinc
US11944640B2 (en) 2016-11-01 2024-04-02 Xylonix PTE. LTD. Zinc-[gamma]-PGA compositions and methods for treating cancer
EP3668318A4 (fr) * 2017-08-17 2021-05-05 Yoram Tsivion Compositions antimicrobiennes
WO2019238892A1 (fr) * 2018-06-15 2019-12-19 Taminco Bvba Traitement de volailles ou de porcs destiné à diminuer l'indice de consommation et/ou à augmenter leur prise de poids
CN112334011A (zh) * 2018-06-15 2021-02-05 塔明克公司 为降低饲料转化率或提高其增重的家禽或猪的处理
CN112334011B (zh) * 2018-06-15 2024-03-29 塔明克私人有限公司 为降低饲料转化率或提高其增重的家禽或猪的处理
CN109430560A (zh) * 2018-12-25 2019-03-08 内蒙古金河动物药业有限公司 一种氧化锌饲料添加剂及其制备方法和应用
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