WO2011069654A1 - Carnitine granulate and methods for its production - Google Patents
Carnitine granulate and methods for its production Download PDFInfo
- Publication number
- WO2011069654A1 WO2011069654A1 PCT/EP2010/007479 EP2010007479W WO2011069654A1 WO 2011069654 A1 WO2011069654 A1 WO 2011069654A1 EP 2010007479 W EP2010007479 W EP 2010007479W WO 2011069654 A1 WO2011069654 A1 WO 2011069654A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carnitine
- aqueous solution
- granulate
- carrier
- mixer
- Prior art date
Links
- 229960004203 carnitine Drugs 0.000 title claims abstract description 92
- 239000008187 granular material Substances 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 title abstract 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000007864 aqueous solution Substances 0.000 claims abstract description 44
- 239000002245 particle Substances 0.000 claims abstract description 28
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 5
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 103
- 239000000243 solution Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 235000013305 food Nutrition 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002537 cosmetic Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 235000013373 food additive Nutrition 0.000 description 6
- 239000002778 food additive Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000001694 spray drying Methods 0.000 description 6
- 241000282412 Homo Species 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- PHIQHXFUZVPYII-LURJTMIESA-N (S)-carnitine Chemical compound C[N+](C)(C)C[C@@H](O)CC([O-])=O PHIQHXFUZVPYII-LURJTMIESA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000003674 animal food additive Substances 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 2
- 229960000678 carnitine chloride Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000012041 food component Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000005417 food ingredient Substances 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940046374 chromium picolinate Drugs 0.000 description 1
- GJYSUGXFENSLOO-UHFFFAOYSA-N chromium;pyridine-2-carboxylic acid Chemical compound [Cr].OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1 GJYSUGXFENSLOO-UHFFFAOYSA-N 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229960001518 levocarnitine Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- -1 sulphate and sodium Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- 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
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- 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
- A23K20/10—Organic substances
-
- 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
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
-
- 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
- A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
-
- 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
- A23P10/10—Securing foodstuffs on a non-edible supporting member
-
- 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
- A23P10/20—Agglomerating; Granulating; Tabletting
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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
-
- 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
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention relates to carnitine granulates and methods for their production.
- Carnitine (vitamin BT; 3-hydroxy-4-trimethylammonio-butanoate) is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy.
- Carnitine exists in two stereoisomers. The biologically active form is L-carnitine, whilst its enantiomer, D-carnitine, is biologically inactive. Pure L-carnitine can be obtained by microbiological processes or by organic synthesis with subsequent purification steps. Due to its vitamin-like function, L-carnitine has a broad range of pharmaceutical, food and cosmetic applications.
- L-carnitine is known to have positive effects on energy metabolism and the cardiovascular, muscular and nervous system of humans and animals. L-carnitine is also useful for other purposes, for instance as a nutrient for yeast and bacteria growth. Carnitine can be administered orally to humans and animals.
- Solid L-carnitine has a high hygroscopy.
- powder mixtures have a low stability, in particular storability, and are only of limited use in industry, especially in the food industry.
- Various attempts have been made in the art to overcome the problem of hygroscopy.
- EP 0434088 B1 suggests using a salt of L-carnitine with L-tartric acid in the preparation of tablets or capsules.
- US 2009/0082449 discloses methods for obtaining carnitine powders or granulates.
- the carnitine is coated on a solid carrier in order to obtain a coated granulate.
- a first method it is suggested to coat the solid carrier with an aqueous carnitine solution by preparing an aqueous suspension and spray-drying.
- a spray-drying process requires large amounts of water in the spray-drying solution. This is problematic, because the water has to be evaporated subsequently, which requires a large amount of energy and also time.
- a second method it is suggested to mix solid carnitine with a solid carrier.
- a liquid solution of a starting material comprising a low amount of carnitine, such as a permeate or a fermentation product is mixed with a carrier and subjected to a drying process in order to obtain a granulate.
- a drying process in order to obtain a granulate.
- relatively large amounts of water have to be used which subsequently have to be removed in an energy and time consuming process.
- the granules tend to form agglomerated particles.
- a method for producing granulates coated with carnitine chloride is disclosed in JP 08-012569. According to this method, aqueous solutions comprising usually 30 to 60% by weight carnitine chloride are admixed with carriers which are preferably silica carriers. After drying, the product can be admixed with organic binders and pressed into tablets and the like.
- the problem underlying the invention is to provide a carnitine granulate and methods for the production of a carnitine granulate, which overcome the above-mentioned problems.
- the invention shall provide a simple and convenient method for obtaining carnitine granulates.
- the method shall require a low number or process steps, low amounts of energy, and shall be carried out during a relatively short time span. Energy intensive steps like spray-drying and drying at high temperatures for extended times shall be avoided.
- a further problem underlying the invention is to provide a carnitine having a low hygroscopy and high flowability.
- the carnitine shall be storable for extended time periods without essential deterioration of the material. Specifically, caking of the carnitine shall be reduced or inhibited even over extended time periods. Further, also mixtures of the carnitine with other components, for instance in a feed product, shall have the desired high flowability and low tendency towards caking. It would be of benefit if the carnitine or carnitine formulations can be stored for a longer period of time without using cost intensive special packing to limit or avoid caking.
- Carnitine is a zwitterion, which comprises a carboxyl group and a quaternary ammonium group.
- the carnitine comprising solution in step (a) is generally obtainable by dissolving carnitine or a salt thereof in water.
- the carnitine used for preparing the solution in step (a) is preferably the zwitterionic carnitine.
- a carnitine salt for preparing the solution such as a chloride, sulphate or nitrate salt.
- the carnitine used in step (a) for providing the aqueous solution is preferably not a salt of a carnitine with an optically active anion.
- a low hygroscopy is obtainable without providing carnitine in the form of a complex salt, for example an organic salt, especially one comprising more than 3 carbon atoms, such as a tartrate or citrate.
- the aqueous solution in step (a) comprises at least 65% (w/w), preferably more than 70%, more than 75% or more than 76.5% (w/w) L-carnitine.
- the solution is close to saturation or a saturated solution or an oversaturated solution.
- the solution is a clear solution.
- aqueous solutions comprising such high levels of L-carnitine are obtainable at enhanced temperature.
- the temperature of the aqueous solution is at least 60°C, preferably at least 70°C or at least 75°C.
- the temperature is between 60 and 90°C, more preferably between 75 and 85°C.
- step (c) the adjustment of such an enhanced temperature is also advantageous, because the formation of stable granules in step (c) is supported. This might be due to the decreased viscosity of the heated solution.
- the solution in step (a) is obtained by providing 15 to 35% (w/w) water in a vessel, adding 65 to 85% (w/w) carnitine or a salt thereof and stirring at elevated temperature until the carnitine is dissolved whilst reducing the viscosity of the solution.
- the aqueous solution in step (a) essentially consists of water and carnitine. Impurities, for example side products from the production process may be present. Based on the total amount of solids in the aqueous solution, the level of non-carnitine solids may be below 5%, below 2% or below 1% (w/w).
- the carnitine is used in combination with at least one other soluble component.
- aqueous solution in step (a) should have a viscosity such that it can be poured or sprayed with common apparatuses.
- the viscosity of the carnitine solution step (a) is between 0.5 to 150 mPas, more preferably between 0.8 and 50 mPas, measured at 70°C, or at the temperature at which solution (a) is prepared.
- the average particle diameter of the particulate carrier is above 150 pm, preferably above 180 pm, above 200 pm or above 220 pm. Surprisingly, it was found that stable granulates, which have a high flowability and low hygroscopy, are obtainable when carriers with large particle diameters are used in the specific process of the invention.
- the average particle diameter (d50) of the carrier is between 150 and 1000 pm, more preferably between 180 and 800 pm or between 220 and 500 pm.
- an optimal carrier size, especially for a food product or food additive is between about 200 and about 300 pm.
- the average particle diameter (d50 pm) can be determined according to ISO 13320:2009. By the method of the invention, also carriers having average particle diameters above 1000 ⁇ can be used, but such products are generally less applicable in pharmaceutical, food or feed applications.
- the ratio of dry carnitine to carrier used as starting compounds in the inventive method is preferably between 0.5:1 and 5:1 or between 1 :1 and 2.5:1 , more preferably between 1.3:1 and 2:1 (w/w).
- the BET surface of the carrier is between 100 and 1000 m 2 /g, more preferably between 150 and 600 m 2 /g or between 200 and 500 m 2 /g as determined by ISO 5794-1.
- the BET surface relates to the specific surface of the particles. In general particles having a high BET surface (m 2 /g) absorb higher amounts of water.
- the carrier used according to the invention comprises silica.
- the carrier is a microgranulated silica carrier.
- Microgranulated silica is known in the art and commercially available.
- the particles are usually more or less spherical.
- the carriers shall be capable of absorbing at least a certain amount of water.
- Such carriers are commercially available for example under the trademark Tixosil from Rhodia or under the trademark SIPERNAT from Evonik Industries.
- useful silica carriers according to the invention are Tixosil 68, Tixosil 38X and SIPERNAT 2200, each having an average particle size above 150 ⁇ .
- the silica carrier essentially consists of SiO 2 .
- the carrier comprises silica in combination with at least one other metal oxide, for example alumina.
- the silica content may be above 10%, above 50% or above 80 % (w/w).
- step (c) the aqueous solution is fed into a mixer containing the carrier whilst the mixer is agitated.
- the mixer can be a common device, such as a vertical mixer, vertical screw mixer, paddle mixer, horizontal mixer or spherical mixer.
- the aqueous solution can be fed into the mixture for example by a spray nozzle or a simple open tube. It is preferred that the feeding of the aqueous solution into the mixer is extended over a certain time interval in order to ensure that the solution is evenly absorbed by the carrier. For example, the feeding of the aqueous solution may be carried out over a period of 20 minutes to 3 hours, preferably between 30 minutes and 2 hours.
- the feeding speed should be adjusted such that the solution can be absorbed effectively by the carrier in order to obtain a uniform coating.
- the aqueous solution is preferably maintained at an enhanced temperature.
- the temperature or temperature range is selected as in step (a).
- the mixer might be heated.
- the overall process can be carried out as a batch process or as a continuous process.
- an anticaking agent is added.
- Anticaking agents are additives which prevent a composition from caking together and thus from forming lumps or a continuous solid.
- an anticaking agent is selected which is acceptable for oral consumption, as necessary in food products or pharmaceuticals.
- an anti-caking agent based on silicon dioxide.
- the anticaking agent is hydrophobic and water-repellent.
- the anticaking agent is hydrophobized silica particles.
- the anticaking agent is a hydrophobized silica granulate, for example with an average particle size below 50 ⁇ , below 30 pm or below 20 pm (d50 as measured by ISO 13320-1 ).
- Such products are known in the art and commercially available, for example under the trademark SIPERNAT D17 or SIPERNAT 22 from Evonik Industries.
- the amount of anticaking agent added is 0.5 to 10%, more preferably 1 to 5% (w/w) based on the total amount of carrier.
- the anticaking agent is added after step (c), i.e. after the aqueous solution and the carrier were mixed, or at least after the addition of at least a major portion of the aqueous solution.
- step (c) the aqueous solution is fed into the mixer during at least two time intervals, between which the feeding is interrupted whilst continuously agitating the mixture.
- the aqueous solution is fed into the mixture during two time intervals.
- Each interval may have a length between 5 minutes to 40 minutes, preferably between 10 minutes to 30 minutes.
- the length of the intermediate interruption may be between 5 to 40 minutes, or between 10 to 30 minutes.
- the length of the interruption should be sufficient that the carnitine solution in the mixer is absorbed, or essentially absorbed, by the carrier.
- the mixture is further agitated for a certain time, for instance for at least two minutes, preferably for 3 to 20 minutes.
- the length of the time intervals, the amount of aqueous solution added during each interval, the amount of carrier and the velocity of the mixer are interrelated and are adjusted such that the solution is evenly absorbed by the carrier.
- step (c) comprises the steps of (c1 ) feeding a first portion of the aqueous solution into the mixer,
- an anticaking agent is added after step (c3) or after or during step (c4),
- the carnitine granulate may be subjected to subsequent processing steps, such as sieving, if desired.
- Subject of the invention is also a carnitine granulate, obtainable by a method of the invention.
- the carnitine granulate is stable and of low hygroscopy.
- Another subject of the invention is a carnitine granulate, wherein the granules essentially consist of a silica carrier coated with carnitine.
- the granules have an average particle size of more than 160 ⁇ ⁇ ⁇ , or more than 200 ⁇ .
- the average granule size may be between 200 and 700 ⁇ , or between 220 and 400 ⁇ .
- the inventive granulate may comprise at least 5% or at least 10% (w/w) carnitine.
- the carnitine granules comprise or essentially consist of between 30 to 95 % (w/w) silica carrier and between 70 to 5 % (w/w) carnitine, based on the total amount of solids.
- the carnitine granules may comprise less than 10%, less than 5 % or less than 2% (w/w) of other components, for example due to the presence of impurities.
- the granulate mainly comprises single carrier particles with a carnitine coating.
- the granules are essentially not agglomerates of coated carrier particles. This ensures the uniformity and high flowability of the inventive granulate.
- the granulate is thus different from the granulate described in section [0093] of US 2009/0082449, the particles of which are agglomerates of coated carrier particles.
- the hygroscopy of the granulate is low. The hygroscopy can be determined by the method of ISO 12571 :2000.
- the granulate of the invention has a good flowability.
- the granulate has a repose angle below 45°, more preferably below 40° or below 35°.
- the repose angle can be determined by the method of DIN ISO 4324.
- the carnitine is pure or essentially pure L-carnitine. Small amounts of D-carnitine may be present due to impurities. In a less preferred embodiment, the carnitine may be a racemate or D-carnitine.
- carnitine granulate of the invention is used in a food, pharmaceutical or cosmetic composition.
- food refers to any food or feed for humans and animals.
- the carnitine granulate may be administered to humans or to animals, for example cattle, horses, pigs, poultry, fish or pets, such as cats and dogs.
- the carnitine granulate can be admixed with addition compounds.
- additional compounds can be substances that are suitable as food ingredients or food additives.
- food ingredient means a single substance or a mixture of substances which optionally can contain one or more additives and which serve for nutrition of human beings and can be consumed by human beings or animals in an unprocessed, processed and/or formulated state.
- a "food additive” is a substance that is added to a foodstuff to alter certain features of this foodstuff such as appearance, constitution, consistency, taste, odour, storability, workability etc. or for physiological or nutritional reasons.
- Examples for food additives include, without being restricted to, sweeteners, bulking agents, flavouring agents, acidifying agents, preservative agents, mineral matter, vitamins, amino acids, antioxidants, enzymes, pigments, emulsifying agents, agents that improve compaction and the like.
- the additional compounds can also be substances or substance mixtures that are conventionally used for the preparation of a pharmaceutical composition, without being themselves active ingredients or agents.
- a "pharmaceutical composition” is a substance or formulation which upon application to or within an animal or human body can cure or heal and/or relieve and/or prevent a certain condition, disease, suffering or injury or which can restore certain functions of a tissue or organ of that body to the normal.
- Substances which are commonly used for the preparation of pharmaceutical compositions and which are not themselves active agents include, without being restricted to, excipients, lubricants, flavouring agents, disintegrants, binding agents and the like.
- the inventive carnitine granulate and the inventive method solve the above mentioned problems.
- the method of the invention allows the preparation of a carnitine granulate in a relatively simple manner.
- the inventive method can be carried out whilst consuming low amounts of energy and in a short time, whilst applying simple standard equipment.
- the process, the solution and the carrier can be adjusted, such that the water used is essentially absorbed by the granules.
- an energy consuming drying step such as a spray-drying step
- the method of the invention does not comprise a spray-drying step.
- drying temperatures above 30°C or above 50°C and/or drying times above 10 or above 30 minutes are not applied.
- dry means that the granules are essentially not wet or moist on the surface. However, they usually have an internal water content, because a portion of the water used in the coating process is adsorbed into the core of the particles.
- the inventive process a carnitine granulate with highly advantageous properties is obtained.
- the carnitine granulate has a low hygroscopy and remains flowable over extended storing time periods. Even when storing the granulate for about 3 months, the flowability is not affected negatively.
- a carnitine granulate having a high average particle size is obtainable, which improves the flowability.
- it is not necessary to introduce stability enhancing additives, such as organic binders, into the granule coatings.
- the inventive carnitine granulate essentially consists of the carnitine, the carrier and the anticaking agent, which is preferably silica-based.
- micro granulated silica (Tixosil 68, Rhodia) are fed into a mixer (e.g. Nauta type or horizontal paddle mixer). The mixer is turned on.
- the carnitine solution will be fed at 75 to 80°C into the running mixer via a spray nozzle or open tube/pipe.
- Silica/carnitine/water is mixed for 15min without feeding of the carnitine/water solution.
- the rest of the aqueous solution is fed in to the mixer within 10 minutes or longer.
- the average particle diameter d50 was about 262 ⁇ .
- the average particle diameter (d50 pm) was determined according to ISO 13320:2009.
- the repose angle of the granulate was determined to be 34.5°, compared to 53.3° of a commercially available feed formulation. The repose angle was determined by the method of DIN ISO 4324.
- the HAUSNER ratio was determined to be 1.18 (indicating free flowing), compared to 1.41 (indicating non-flowing) of a commercially available feed formulation.
- the HAUSNER ratio was determined according to DIN 53194.
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012542397A JP5911806B2 (ja) | 2009-12-11 | 2010-12-09 | カルニチン顆粒およびその製造方法 |
CN201080056055.4A CN102651974B (zh) | 2009-12-11 | 2010-12-09 | 肉碱颗粒及其制备方法 |
EP10790620.8A EP2509436B1 (en) | 2009-12-11 | 2010-12-09 | Carnitine granulate and methods for its production |
ES10790620.8T ES2579964T3 (es) | 2009-12-11 | 2010-12-09 | Granulado de carnitina y métodos para su producción |
KR1020127017960A KR101761958B1 (ko) | 2009-12-11 | 2010-12-09 | 카르니틴 과립 및 이의 제조 방법 |
IN4941DEN2012 IN2012DN04941A (ko) | 2009-12-11 | 2012-06-05 | |
HK12110094.0A HK1169280A1 (en) | 2009-12-11 | 2012-10-12 | Carnitine granulate and methods for its production |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28580509P | 2009-12-11 | 2009-12-11 | |
EP09015339A EP2335495A1 (en) | 2009-12-11 | 2009-12-11 | Carnitine granulate and methods for its production |
US61/285805 | 2009-12-11 | ||
EP09015339.6 | 2009-12-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011069654A1 true WO2011069654A1 (en) | 2011-06-16 |
Family
ID=41691995
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/007479 WO2011069654A1 (en) | 2009-12-11 | 2010-12-09 | Carnitine granulate and methods for its production |
Country Status (11)
Country | Link |
---|---|
US (2) | US8470382B2 (ko) |
EP (2) | EP2335495A1 (ko) |
JP (2) | JP5911806B2 (ko) |
KR (1) | KR101761958B1 (ko) |
CN (1) | CN102651974B (ko) |
AR (1) | AR079439A1 (ko) |
ES (1) | ES2579964T3 (ko) |
HK (1) | HK1169280A1 (ko) |
IN (1) | IN2012DN04941A (ko) |
TW (1) | TWI469797B (ko) |
WO (1) | WO2011069654A1 (ko) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014024793A (ja) * | 2012-07-26 | 2014-02-06 | Rohto Pharmaceut Co Ltd | 内服用固形製剤の吸湿性・流動性の改善方法、吸湿性・流動性が改善されてなる内服用固形製剤、及び該内服用固形製剤の製造法 |
KR20140051936A (ko) * | 2011-07-08 | 2014-05-02 | 푸락 바이오켐 비.브이. | 사료 산물에 사용하기 위한 활성 제형 |
JP2016106125A (ja) * | 2016-02-26 | 2016-06-16 | ロート製薬株式会社 | 内服用固形製剤の吸湿性・流動性の改善方法、吸湿性・流動性が改善されてなる内服用固形製剤、及び該内服用固形製剤の製造法 |
WO2022258631A1 (en) | 2021-06-07 | 2022-12-15 | Kaesler Nutrition Gmbh | Carnitine formulation |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL169678A (en) | 2005-07-14 | 2010-11-30 | Innova Sa | Sweetener compositions |
EP2335495A1 (en) * | 2009-12-11 | 2011-06-22 | Lonza Ltd. | Carnitine granulate and methods for its production |
US10231476B2 (en) | 2014-04-04 | 2019-03-19 | Douxmatok Ltd | Sweetener compositions and foods, beverages, and consumable products made thereof |
US10207004B2 (en) * | 2014-04-04 | 2019-02-19 | Douxmatok Ltd | Method for producing sweetener compositions and sweetener compositions |
US20160242439A1 (en) | 2014-04-04 | 2016-08-25 | Douxmatok Ltd | Method for producing sweetener compositions and sweetener compositions |
US20170223988A1 (en) * | 2014-07-31 | 2017-08-10 | Benemilk Oy | Coated feed compositions and methods of making and using thereof |
CN106901042A (zh) * | 2017-04-27 | 2017-06-30 | 上海美嘉饲料有限公司 | 一种提高种公猪精子活力的饲料添加剂 |
JP7235501B2 (ja) * | 2017-12-28 | 2023-03-08 | アリナミン製薬株式会社 | ビタミンb1類及びカルニチン類を含有する顆粒 |
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WO2007003425A2 (en) * | 2005-07-05 | 2007-01-11 | Lonza Ag | Spray-drying process for producing a dry carnitine powder or granulate |
EP2008531A1 (en) * | 2006-03-15 | 2008-12-31 | Suntory Limited | Composition for foods and drinks having improved hygroscopicity |
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CN101120935A (zh) * | 1999-09-03 | 2008-02-13 | 希格马托健康科学股份公司 | 超细l-肉碱、其制备方法、含有它的组合物及其使用方法 |
EP2335495A1 (en) * | 2009-12-11 | 2011-06-22 | Lonza Ltd. | Carnitine granulate and methods for its production |
-
2009
- 2009-12-11 EP EP09015339A patent/EP2335495A1/en not_active Ceased
-
2010
- 2010-12-09 ES ES10790620.8T patent/ES2579964T3/es active Active
- 2010-12-09 WO PCT/EP2010/007479 patent/WO2011069654A1/en active Application Filing
- 2010-12-09 EP EP10790620.8A patent/EP2509436B1/en active Active
- 2010-12-09 US US12/964,187 patent/US8470382B2/en active Active
- 2010-12-09 KR KR1020127017960A patent/KR101761958B1/ko active IP Right Grant
- 2010-12-09 JP JP2012542397A patent/JP5911806B2/ja active Active
- 2010-12-09 CN CN201080056055.4A patent/CN102651974B/zh active Active
- 2010-12-10 AR ARP100104597A patent/AR079439A1/es unknown
- 2010-12-10 TW TW99143177A patent/TWI469797B/zh active
-
2012
- 2012-06-05 IN IN4941DEN2012 patent/IN2012DN04941A/en unknown
- 2012-10-12 HK HK12110094.0A patent/HK1169280A1/xx not_active IP Right Cessation
-
2013
- 2013-06-03 US US13/908,645 patent/US9066868B2/en active Active
-
2015
- 2015-12-25 JP JP2015254564A patent/JP6239579B2/ja active Active
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20140051936A (ko) * | 2011-07-08 | 2014-05-02 | 푸락 바이오켐 비.브이. | 사료 산물에 사용하기 위한 활성 제형 |
KR102196004B1 (ko) * | 2011-07-08 | 2020-12-31 | 푸락 바이오켐 비.브이. | 사료 산물에 사용하기 위한 활성 제형 |
JP2014024793A (ja) * | 2012-07-26 | 2014-02-06 | Rohto Pharmaceut Co Ltd | 内服用固形製剤の吸湿性・流動性の改善方法、吸湿性・流動性が改善されてなる内服用固形製剤、及び該内服用固形製剤の製造法 |
JP2016106125A (ja) * | 2016-02-26 | 2016-06-16 | ロート製薬株式会社 | 内服用固形製剤の吸湿性・流動性の改善方法、吸湿性・流動性が改善されてなる内服用固形製剤、及び該内服用固形製剤の製造法 |
WO2022258631A1 (en) | 2021-06-07 | 2022-12-15 | Kaesler Nutrition Gmbh | Carnitine formulation |
Also Published As
Publication number | Publication date |
---|---|
KR20120104315A (ko) | 2012-09-20 |
US9066868B2 (en) | 2015-06-30 |
TW201127407A (en) | 2011-08-16 |
JP2013513557A (ja) | 2013-04-22 |
TWI469797B (zh) | 2015-01-21 |
EP2335495A1 (en) | 2011-06-22 |
EP2509436B1 (en) | 2016-04-06 |
JP2016117736A (ja) | 2016-06-30 |
CN102651974B (zh) | 2015-04-01 |
HK1169280A1 (en) | 2013-01-25 |
EP2509436A1 (en) | 2012-10-17 |
US20130273165A1 (en) | 2013-10-17 |
AR079439A1 (es) | 2012-01-25 |
JP5911806B2 (ja) | 2016-04-27 |
CN102651974A (zh) | 2012-08-29 |
IN2012DN04941A (ko) | 2015-09-25 |
US20110190394A1 (en) | 2011-08-04 |
ES2579964T3 (es) | 2016-08-17 |
JP6239579B2 (ja) | 2017-11-29 |
KR101761958B1 (ko) | 2017-07-26 |
US8470382B2 (en) | 2013-06-25 |
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