US20030176514A1 - Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate - Google Patents

Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate Download PDF

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US20030176514A1
US20030176514A1 US10/362,730 US36273003A US2003176514A1 US 20030176514 A1 US20030176514 A1 US 20030176514A1 US 36273003 A US36273003 A US 36273003A US 2003176514 A1 US2003176514 A1 US 2003176514A1
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Prior art keywords
carnitine
mixture
acid
weight
magnesium
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US10/362,730
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Martin Fuhrmann
Daniel Pianzola
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Lonza AG
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Lonza AG
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Assigned to LONZA AG reassignment LONZA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FUHRMANN, MARTIN, PIANZOLA, DANIEL
Publication of US20030176514A1 publication Critical patent/US20030176514A1/en
Priority to US10/785,013 priority Critical patent/US7230131B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A23L33/165—Complexes or chelates
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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 present application relates to a novel method for preparing a mixture which can be granulated and which is suitable for pharmaceutical dosage forms or for dietary supplementation, comprising at least one hygroscopic substance, preferably L-carnitine.
  • the application further relates to such novel mixtures that can be granulated, comprising salts of carnitine, at least one alkali metal or alkaline earth metal cation, and an organic, physiologically acceptable acid.
  • the present invention further relates to a carnitine-magnesium hydroxycitrate.
  • L-( ⁇ )-Carnitine plays an important part in energy metabolism, in the breakdown of fatty acids, in the eukaryotic organism. It is a vitamin-like substance which has been admixed to food products or administered as dietary supplement or pharmaceutical dosage form for some time to prevent and treat manifestations of deficiency. Such manifestations of deficiency may occur in particular in children and elderly people or when the diet is unbalanced. Magnesium and citrate are likewise physiological substances; manifestations of deficiency due to inadequate intake of magnesium in particular are not rare. They can be prevented by taking Mg products. Citrate is utilized without difficulty in energy metabolism. The muscle tissue of a healthy adult contains approximately 20 g of magnesium and 20 g of L-carnitine. A healthy adult can take about 2 g of L-carnitine additionally each day for optimal energy supply. Since carnitine and magnesium are required for metabolic processes which are closely associated, a combination product has a beneficial synergistic effect.
  • L-carnitine is very hygroscopic. This is the cause of a lack of storability of the solid substance and of simple powder mixtures prepared therefrom, and causes problems such as inadequate flowability during the further processing of pure solid carnitine or powdered mixtures containing carnitine in the human food, animal feed or drugs industry.
  • EP 402 755 describes the stoichiometric complex salt L-carnitine-magnesium citrate which is distinctly less hygroscopic than free carnitine and is thus stable on storage. At a relative humidity of 56%, the water uptake by the complex salt after storage for 1 week is 21% by weight.
  • the complex salt is prepared by mixing the components in aqueous solution at 60° C. The solid is then obtained by spray drying or crystallization. The residual hygroscopicity of the carnitine-magnesium citrate prepared in this way still proves to be a certain problem during storage and further processing. A further reduction is desirable.
  • Salts which, besides carnitine, comprise exclusively hydroxy acids such as, for example, tartaric acid, without involvement of metal ions, and which are in a similar way less hygroscopic than pure carnitine are also known. All known methods of preparation without exception require the use of relatively large amounts of water or aqueous solvents and, for the crystallization, also organic solvents. The drying methods, e.g. spray drying, require a considerable energy input or the use of organic solvents. The latter is associated with additional costs and the problem of disposal of the waste solvents.
  • the mixture comprises at least one hygroscopic substance, preferably L-carnitine
  • the solid hygroscopic substance in a first stage the solid hygroscopic substance is mixed with at least one organic acid and at least one metal hydroxide without addition of water or with addition of not more than 15% by weight of water, and in a second, subsequent stage the water content of the resulting mixture is reduced by drying to below 5% by weight, with the resulting composition preferably remaining viscous and, where appropriate, being solidified in a further step of the method.
  • Addition of water means in this connection for the purposes of the present invention the water added in liquid form to the mixture in its entirety, excluding the water of reaction from the neutralization reaction between acid and hydroxide. It can be added as separate liquid, but it can also serve as solvent or suspending agent for example for the acid or the hydroxide; such a solution or suspension can then be added to the mixing process.
  • the organic acid and the metal hydroxide are starting substances which are solid per se and which add to the mixture no additional water apart from water of crystallization which is possibly present.
  • Solid starting substances mean for the purposes of the present invention preferably free-flowing substances which are in the form of coarse granules or fine powder.
  • a hygroscopic substance means for the purposes of the present invention a substance which on storage under standard conditions is prone to conglutination or deliquescence through uptake of water.
  • substances which on storage at a relative humidity of 56% under standard conditions show a weight gain of more than 20% after 1 week are regarded as hygroscopic substances within the meaning of the present application. Examples of such hygroscopic substances are carnitine and creatine, which bind moisture strongly.
  • carnitine chloride or an alkanoylcarnitine in particular acetylcarnitine.
  • alkanoylcarnitine is preferably in the physiological L-( ⁇ ) form, However, it is also possible to use racemic DL-carnitine.
  • An organic acid or an acid residue means in the sense of the present application in particular physiologically acceptable monobasic or polybasic organic acids, in particular biogenic hydroxy acids or fruit acids and their derivatives such as, for example, ascorbic acid (vitamin C), tartaric acid, malic acid, pyruvic acid, hydroxypyruvic acid, fumaric acid, glutaric acid, citric acid, ( ⁇ )-hydroxycitric acid or isocitric acid, aspartic acid, glutamic acid, succinic acid, as are customary and approved for example in effervescent tablets and for use in food products or medicaments.
  • vitamin C ascorbic acid
  • malic acid pyruvic acid
  • hydroxypyruvic acid fumaric acid
  • glutaric acid citric acid
  • ( ⁇ )-hydroxycitric acid or isocitric acid aspartic acid
  • glutamic acid glutamic acid
  • succinic acid as are customary and approved for example in effervescent tablets and for use in food products or medicaments.
  • a metal hydroxide means for the purposes of the present invention preferably those hydroxides which are in solid form, for example alkali metal hydroxides or, in a particularly preferred embodiment, alkaline earth metal hydroxides.
  • the alkaline earth elements are expediently physiologically acceptable, such as calcium or magnesium, which occur in the mammalian organism in considerable quantity.
  • a composition which can be granulated and has been prepared by the method of the invention is surprisingly distinguished by a particularly low hygroscopicity compared with the starting substance, for example pure carnitine.
  • a further advantage of the method of the invention is the avoidance of the addition of large amounts of water, so that eventually costly removal of the residual moisture from the final product is necessary, and the simple manner of preparation which requires no additional processing steps.
  • the use of a metal hydroxide together for example with citric acid or another organic acid leads in a neutralization reaction advantageously and directly to an optimal distribution of the water of reaction from the neutralization between the solids particles, and thus permits minimization of the addition of water and suitable flow properties of the powdered or pasty composition.
  • the content of added water in the mixture is not more than 3%, and in a particularly preferred embodiment is not more than 1% by weight, and in the most preferred embodiment no additional water is admixed.
  • mixing apparatuses known per se to the skilled worker, such as, for example, kneading machines like those normally used for solid or pasty substances. It is also possible for example to use suitable extruders such as, for example, a twin screw extruder. Kneading machines are preferably used as mixing apparatus. The drying can then be carried out directly in the equipment and be carried out to a desired degree of predrying or else to complete drying.
  • Such apparatuses expediently have suitable control devices to control the product temperature, because the initial neutralization reaction between acid and metal hydroxide may lead to evolution of much heat.
  • the product temperature during the mixing process in the first stage should essentially be, apart from a short initial period, 50° C.-120° C. In a preferred embodiment of the method, the product temperature in the first stage should essentially be 70° C.-120° C. It is preferred first to mix the acid component with the hydroxide component and, after the neutralization reaction, to admix the hygroscopic substance or the carnitine.
  • the product temperature on addition of the hygroscopic substance or the carnitine should be at least 50° C., preferably at least 70° C., during the first stage of the method.
  • the reaction preferably lasts no more than one hour. It is expedient to mix the organic acid and the metal hydroxide in stoichiometric amounts. The combination of heat, finely dispersed solids and a small content of water as solvent leads to a free-flowing, mixable composition.
  • L-carnitine, magnesium hydroxide and citric acid are mixed in stoichiometric amounts, i.e. in a molar ratio of approximately 1:1:1.
  • the types of these substances are preferably sufficiently pure, i.e. approved for the manufacture of food products or the preparation of pharmaceuticals, as are described, for example, in the European Pharmacopoeia. Anhydrous types are expediently used.
  • the pure L-carnitine is preferably added to the mixture as neutral inert salt. Compared with previous methods of preparation, the hygroscopicity of the complex salt L-carnitine-magnesium citrate prepared in this way is reduced further.
  • the moisture uptake determined by gravimetry in the way familiar to the skilled worker, of solid carnitine-Mg citrate prepared by the method of the invention and previously dried to constant weight under oil-pump vacuum or over phosphorus pentoxide is not more than 7% by weight after 48 h at 56% relative humidity (rH). This figure is not exceeded even after storage for 330 h.
  • carnitine content Based on the amount of carnitine or carnitine derivative present in the mixture, referred to within the scope of the invention as carnitine content based on free base, this corresponds to a moisture uptake of not more than 40% by weight. It is preferred for at least 80% of the carnitine-Mg citrate, based on the carnitine content in the mixture, to be in the form of complex salt in the mixture of the invention.
  • a complex salt from carnitine, magnesium hydroxide and hydroxycitric acid (HCA).
  • HCA hydroxycitric acid
  • HCA has a special function as agent promoting breakdown of fats.
  • Such a combination is particularly advantageous because the advantageous material properties of the complex salt is associated with the synergistic cooperation of the latter's components.
  • the method of the invention also permits mixtures of salts which crystallize only poorly using known methods, such as, for example, L-carnitine and ascorbic acid, to be prepared.
  • the reduction of the water content of the pasty mixture preferably takes place by drying in vacuo at a minimum of 85° C., in a most preferred embodiment at a minimum of 90° C., and a maximum of 120° C., and takes place under a pressure extending to 25 mbar, preferably not more than 50 mbar.
  • the drying may, depending on the amount of product, take up to about 3 h.
  • the composition produced in this way is still, despite its increase in solidification as the water content decreases, flowable or pasty to a very limited extent.
  • pasty is thus regarded as a composition which is flowable only under elevated pressure (>1 bar) and at a minimum of 85° C., in the sense of flow characteristics referred to as extrusion viscosity.
  • the pasty composition is movable in the hot state by suitable apparatuses with an adequate torque.
  • Definitive solidification takes place only through cooling. It is possible to expedite the cooling by methods known per se, for example extrusion as thin strand and/or solidification on a cooling belt. It is also possible to add an additional after-drying step during or after the cooling process, for example a further vacuum drying.
  • the product can be coarsely comminuted for further processing and sent for a final granulation or fine granulation. It may in a preferred embodiment of the present method be comminuted to a particle size not exceeding 1 mm using apparatuses known per se to the skilled worker.
  • the comminution is carried out with screening granulators (from FREWITT) and, on use of an extruder with suitable die plates, preferably directly on the coarse granules produced by the extruder without an additional interpolated comminution step.
  • coenzymes such as niacin or niacinamide or other substances which promote growth or the breakdown of fats and which may cooperate synergistically with L-carnitine, such as ⁇ -hydroxy- ⁇ -methylbutyrates, ( ⁇ )-hydroxycitrate, lipoic acid or lipotrophic substances such as lecithin or choline.
  • L-carnitine such as ⁇ -hydroxy- ⁇ -methylbutyrates, ( ⁇ )-hydroxycitrate, lipoic acid or lipotrophic substances such as lecithin or choline.
  • Ca 2+ like Mg 2+ are required for muscle activity, so that this results in a suitable synergistic effect with the effect of carnitine or else creatine which promotes muscle activity and energy metabolism.
  • the present application further relates to a mixture that can be granulated, preferably for dietary supplementation or for pharmaceutical dosage, comprising salts of carnitine, preferably L-carnitine, at least one alkali metal or alkaline earth metal and one physiologically acceptable organic acid, characterized in that the water uptake of the previously dried mixture at a relative humidity of 56° C. under atmospheric pressure and at 25° C. is not more than 15% by weight, preferably not more than 10% by weight, and in a most preferred embodiment not more than 7% by weight, after 24 h, and preferably also after 14 days. Based on the carnitine content of the mixture, the water uptake by the previously dried mixture does not exceed 40% by weight.
  • Drying means in this connection drying over phosphorus pentoxide to constant weight at 25° C.
  • Salts mean in this connection all possible salt compounds between in each case at least two of the substances present in the mixture of the invention.
  • Such a mixture can be prepared by the method of the invention and identifies itself by a particularly low hygroscopicity. Especially with carnitine-magnesium citrate or hydroxycitrate, the latter is further reduced by comparison with the type produced using the previous method of preparation.
  • the organic acid or the acid residue present in the mixture is preferably a citrate, a ( ⁇ )-hydroxycitrate or an ascorbate and, preferably, the alkaline earth metal is calcium, magnesium or a mixture of the two.
  • the acid residue and the alkaline earth metal cation are, in a preferred embodiment, present in stoichiometrically equivalent amounts.
  • the mixture additionally contains at least one other substance from the group consisting of ribose, niacin, niacinamide, ⁇ -hydroxy- ⁇ -methylbutyrate, lipoic acid, coenzyme Q 10 and chromium(III) salts, for example chromium picolinates or chromium nicotinates.
  • the present invention further relates to a mixture for dietary supplementation comprising L-carnitine or an alkanoyl carnitine, coenzyme Q and ⁇ -hydroxy- ⁇ -methylbutyrate and, optionally, ( ⁇ )-hydroxycitrate. It may also comprise a combination of various carnitine salts including the inner salts or of the carnitine derivatives and the salts thereof.
  • a mixture is novel and can likewise be prepared in a solids-mixing method of the invention, for example using an extruder, as mixture that can be granulated. Such a mixture can, however, also be prepared in another known method.
  • the organic acids present in this mixture may be present in the mixture in the protonated form or as salt with a counterion.
  • the carnitine or carnitine derivative can be present in the mixture as complex salt or as inner salt or as salt with a counterion.
  • the mixture of the invention comprises both substances which promote burning up of fats or mobilization of the body fat and substances which inhibit the neosynthesis of fat and fatty acids.
  • Such a mixture can be used in particular as dietary supplement assisting the breakdown of body fat or, as part of a diet, as constituent of food substitute preparations or weight-loss agents.
  • Carnitine i.e. in its physiologically active form the L-( ⁇ ) enantiomer, promotes the transport of fat and of the basic metabolic building block acetyl-CoA through cell membranes to the site of utilization in energy metabolism, the mitochondrial matrix. Carnitine thus increases the substance flux during the beta oxidation of fatty acids.
  • Ubiquinone or coenzyme Q preferably coenzyme Q 10
  • the combination of carnitine and ubiquinone thus represents an advantageous cumulative cooperation of two principles of action.
  • ( ⁇ )-Hydroxycitrate inhibits ATP-citrate lyase.
  • ⁇ -Hydroxy- ⁇ -methylbutyrate reduces, through substrate inhibition, the availability of acetyl-CoA, the central cofactor in fatty acid and cholesterol biosynthesis.
  • coenzyme Q has the function, in the mixture stored in the dry, of an antioxidant promoting storage stability.
  • Q10 means the differentiation customary in biochemistry of the biogenic ubiquinones through the length of the isoprenyl side chains, the species with 10 carbon atoms in the side chain being the species which is most frequently represented in most mammals, including humans.
  • the mixture of the invention with other ubiquinones physiologically active in humans, as can be obtained for example from microorganisms.
  • the predominant coenzyme Q species in yeast S. cerevisiae
  • Q6 (6 carbon atoms).
  • Such a mixture may comprise at least one or, in any combination, a plurality of substances from the group consisting of vitamin C, lipoic acid, vitamin E, ribose, niacin, niacinamide, creatin and Cr(III) salts, preferably Cr picolinate or Cr nicotinate.
  • the substances are well known from sports and health diets and play either a part in energy metabolism or fat utilization, the mobilization of the body's reserves or, as cellular antioxidants, have a protective function in relation to an increased energy metabolism.
  • ( ⁇ )-hydroxycitric acid which can be obtained as predominant fruit acid from fruits of the genus Garcinia, is another component of the mixture in the most preferred embodiment.
  • Preferred practical embodiments of the mixture of the invention, and of other salts or mixtures of the present invention are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain, for example, 10-1 000 mg of carnitine (or a derivative), 10-1 000 mg of coenzyme Q and 10-1 000 mg of ⁇ -hydroxy- ⁇ -methylbutyrate.
  • a conventional hard gelatin two-piece capsule may contain 300 mg of each of the three substances of the invention, mixed with colors and microcrystalline cellulose as carrier. It is, however, also possible to add these substances in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc.
  • the present invention further relates to carnitine-magnesium hydroxycitrate.
  • This is a salt of low hygroscopicity and can be prepared by the present method through mixing magnesium hydroxide, hydroxycitric acid and carnitine or alkanoyl carnitine in the molar ratio 1:1:1. It is a neutral salt in the stoichiometric composition, in relation to the charge distribution and the ionizable functional groups.
  • Hydroxycitrate means for the purposes of the present application preferably the ( ⁇ ) enantiomer as described (Lewis, Y. et al., Water extract of ( ⁇ )Hydroxy-Citric acid from fruit of Garcinia Cambogia, Phytochemistry (1965), 4, p.
  • the salt can preferably be used within the meaning of the above statements as weight-loss agent, to promote breakdown of body fat.
  • weight-loss agent to promote breakdown of body fat.
  • hydroxycitrate as such as weight-loss agent and suitable dosages are described for example in U.S. Pat. No. 5,783,603.
  • the novel mixed salt of the invention assists, at least on oral administration, in a surprising, more than just additive, way the occurrence of the desired breakdown of fats and weight loss. This involves a synergistic effect of the mixture in the form of a complex salt.
  • HCA is prone to spontaneous lactonization in aqueous solution and in the gastrointestinal tract.
  • the complexation with Mg before preparation of a solution might have a stabilizing effect in relation to the unwanted rearrangement of the lactone and thus bring about much greater activity in cooperation with carnitine.
  • the salt of the invention at least shows an improved storage stability, in relation to the rearrangement of HCA to the lactone, compared with known HCA salts under standard test conditions customary in the pharmaceutical sector.
  • HCA Hydroxycitric acid
  • CPT carnitine palmitoyltransferase I
  • Malonyl CoA is an important allosteric inhibitor of this enzyme.
  • CPT is important for the transport function of carnitine for fatty acids through the mitochondrial membrane and may, if the activity is inadequate, be limiting for carnitine-mediated transport and thus for fatty acid oxidation in the mitochondria.
  • malonyl CoA is a direct precursor for the biosynthesis of fatty acids and cholesterol.
  • the site of action of HCA is the enzyme citrate lyase which is competitively inhibited by HCA.
  • the affinity of the enzyme for HCA is more than 100 times higher than for the natural metabolic substrate citric acid.
  • the lactone derivative to which HCA spontaneously cyclizes has a clear lower affinity by comparison.
  • Preferred practical implements of the mixture of the invention are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain for example 10-2 000 mg of carnitine-magnesium hydroxycitrate.
  • a conventional hard gelatin two-piece capsule may contain 1 000 mg of carnitine-magnesium hydroxycitrate mixed with colors and microcrystalline cellulose as carrier.
  • the substance of the invention in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc. It is also possible to use carnitine-magnesium hydroxycitrate mixed with ⁇ -hydroxy- ⁇ -methylbutyrate or other aforementioned substances.
  • Preparation takes place in the method described in example 2, mixing 83 g of carnitine (free base), 137 g of ( ⁇ )-hydroxycitric acid HCA-650 77.7%, 30 g of Mg hydroxide and 55 g of water.
  • the weight gain of the mixture of the invention which had previously been dried was, after 24 h under standard conditions, 0.82% by weight. At a relative humidity of 56%, the water uptake of the mixture determined by gravimetry was ⁇ 10% by weight after 30 h, corresponding to about 30% by weight based on the carnitine content of the mixture.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025544A1 (en) * 2003-09-11 2005-03-24 Glykon Technologies Group, Llc Enteric delivery of (-)-hydroxycitric acid
US20070142469A1 (en) * 2005-12-19 2007-06-21 Thomas Debra L Method of using beta-hydroxy-beta-methylbutyrate
US8609725B2 (en) 2004-03-26 2013-12-17 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate for reducing tumor growth rate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20030831A1 (it) 2003-04-22 2004-10-23 Laboratorio Chimico Int Spa Sale basico dell'acido tiottico con la l-carnitina.
EP1734974A1 (de) * 2004-03-18 2006-12-27 Tanabe Seiyaku Co., Ltd. D-ribose zur verbesserung von depressionsartigen symptomen
AU2006265280B2 (en) 2005-07-05 2011-07-14 Lonza Ag Spray-drying process for producing a dry carnitine powder or granulate
US20070072910A1 (en) * 2005-09-29 2007-03-29 Smith Michael L Compositions and methods for lowering plasma concentrations of low density lipoproteins in humans
CN101209975B (zh) * 2006-12-29 2010-12-01 沈阳科硕营养科技有限公司 左旋肉碱富马酸钙及其制备方法与用途
EP2206440A1 (de) * 2008-12-24 2010-07-14 Taminco Verfahren zum Herstellen eines rieselfähigen Pulvers, das eine zerfließende quartäre Ammoniumverbindung enthält
PE20121730A1 (es) 2010-01-29 2013-01-13 Abbott Lab Liquidos nutricionales envasados asepticamente que comprenden beta-hidroxi-beta-metilbutirato (hmb)
US9693577B2 (en) 2010-01-29 2017-07-04 Abbott Laboratories Method of preparing a nutritional powder comprising spray dried HMB
CN102711524B (zh) 2010-01-29 2014-09-10 雅培制药有限公司 包含hmb钙的营养乳剂
TWI526161B (zh) 2010-06-10 2016-03-21 亞培公司 包含鈣ｈｍｂ及可溶性蛋白質之實質上透明營養液

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4602039A (en) * 1983-12-28 1986-07-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Salts of-carnitine and alkanoyl L-carnitines and process for preparing same
US5071874A (en) * 1989-06-14 1991-12-10 Lonza Ltd. L-carnitine magnesium citrate
US5780451A (en) * 1994-04-01 1998-07-14 Abbott Laboratories Nutritional product for a person having ulcerative colitis
US6051608A (en) * 1997-04-30 2000-04-18 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Solid compositions suitable for oral administration comprising L-carnitine or alkanoyl-L-carnitine magnesium fumarate

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1153640A (en) * 1967-04-10 1969-05-29 Soc D Etudes Prod Chimique A Carnitin Salt
IT1172394B (it) * 1983-12-28 1987-06-18 Sigma Tau Ind Farmaceuti Sali della l-carnitina e di alcuni alcanoil derivati della l-carnitina e procedimento per la loro preparazione
WO1996036585A1 (en) * 1995-05-15 1996-11-21 Sabinsa Corporation A new process for the production of potassium hydroxy citric acid, and compositions containing the potassium hydroxy citric acid
IT1276253B1 (it) * 1995-12-15 1997-10-27 Sigma Tau Ind Farmaceuti Composizione farmaceutica contenente l-carnitina o alcanoil l-carnitine per la prevenzione ed il trattamento di stati morbosi
US5817329A (en) * 1997-02-28 1998-10-06 Gardiner; Paul T. Nutritional supplement for increased muscle size and strength for body builders
IT1291134B1 (it) * 1997-04-08 1998-12-29 Sigma Tau Ind Farmaceuti Composizioni solide atte alla somministrazione orale comprendenti una alcanoil l-carnitina magnesio citrato

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4602039A (en) * 1983-12-28 1986-07-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Salts of-carnitine and alkanoyl L-carnitines and process for preparing same
US5071874A (en) * 1989-06-14 1991-12-10 Lonza Ltd. L-carnitine magnesium citrate
US5780451A (en) * 1994-04-01 1998-07-14 Abbott Laboratories Nutritional product for a person having ulcerative colitis
US6051608A (en) * 1997-04-30 2000-04-18 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Solid compositions suitable for oral administration comprising L-carnitine or alkanoyl-L-carnitine magnesium fumarate

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005025544A1 (en) * 2003-09-11 2005-03-24 Glykon Technologies Group, Llc Enteric delivery of (-)-hydroxycitric acid
US20060292216A1 (en) * 2003-09-11 2006-12-28 Clouatre Dallas L Enteric delivery of (-)-hydroxycitric acid
US8609725B2 (en) 2004-03-26 2013-12-17 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate for reducing tumor growth rate
US8778994B2 (en) 2004-03-26 2014-07-15 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate and fatty acids for treating disease-associated wasting
US8778993B2 (en) 2004-03-26 2014-07-15 Abbott Laboratories Method of using β-hydroxy-β-methylbutyrate for the treatment of disease conditions
US8785496B2 (en) 2004-03-26 2014-07-22 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate for treating disease-associated wasting
US8785495B2 (en) 2004-03-26 2014-07-22 Abbott Laboratories Compositions including beta-hydroxy-beta-methylbutyrate
US20070142469A1 (en) * 2005-12-19 2007-06-21 Thomas Debra L Method of using beta-hydroxy-beta-methylbutyrate
US8778992B2 (en) 2005-12-19 2014-07-15 Abbott Laboratories Method of using beta-hydroxy-beta-methylbutyrate to treat allergies and asthma
US8796333B2 (en) 2005-12-19 2014-08-05 Abbott Laboratories Method of using β-hydroxy-β-methylbutyrate to treat a condition

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JP4668513B2 (ja) 2011-04-13
EP1326502B1 (de) 2005-05-18
PT1326502E (pt) 2005-09-30
WO2002017735A3 (de) 2002-09-12
AU2001289849A1 (en) 2002-03-13
EP1326502A2 (de) 2003-07-16
US7230131B2 (en) 2007-06-12
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DE50106272D1 (de) 2005-06-23
JP2004507479A (ja) 2004-03-11

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