EP1345502A1 - Creatine/citric acid compound, method for the production of the same and the use thereof - Google Patents

Creatine/citric acid compound, method for the production of the same and the use thereof

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Publication number
EP1345502A1
EP1345502A1 EP01272630A EP01272630A EP1345502A1 EP 1345502 A1 EP1345502 A1 EP 1345502A1 EP 01272630 A EP01272630 A EP 01272630A EP 01272630 A EP01272630 A EP 01272630A EP 1345502 A1 EP1345502 A1 EP 1345502A1
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Prior art keywords
citric acid
creatine
water
temperatures
formulation
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EP01272630A
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German (de)
French (fr)
Inventor
Ralf JÄGER
Martin Purpura
Günter Ortenburger
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Evonik Operations GmbH
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Degussa GmbH
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Publication of EP1345502A1 publication Critical patent/EP1345502A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • 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
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Creatine / citric acid compound process for its preparation and use
  • the present application relates to creatine / citric acid compounds, their preparation and suitable formulations and their corresponding use.
  • Creatine is primarily found in muscle and nerve tissue and, in the form of its metabolic secondary product, phosphocreatine, is an important energy reserve for the muscle and brain.
  • creatine appears to have a prophylactic and therapeutic effect in ischemia, such as that described in B. caused by inf rct events or by pre- and perinatal oxygen deficit conditions.
  • Creatine has been known as a muscle substance for over 100 years, and it serves as a source of energy for the muscle.
  • creatine is not only a valuable nutritional supplement, but also has valuable therapeutic properties.
  • a number of scientific studies have shown that the controlled intake of creatine over a longer period of time can lead to a significant increase in muscle mass and muscle performance as well as strength and endurance.
  • creatine in a wide variety of application forms (e.g. oral, intravenous, etc.) requires high bioavailability and therefore good water solubility. However, this is usually not sufficient for creatine, which is present as an amino acid derivative in the form of an inner salt, which is why the creatine benefits from its undisputed advantages Supplements and therapies mostly achieved through one of its physiologically tolerable creatine salts.
  • Citric acid is a tricarboxylic acid that is known to be common in the plant kingdom as well as in many animal tissues and body fluids. Citric acid counts u. a. to the series of prominent compounds that are involved in the physiological oxidation of fats, proteins and carbohydrates to carbon dioxide and water (see, inter alia, tricarboxylic acid cycle).
  • Citric acid which was first isolated from lime juice by the Swedish chemist Karl Wilhelm Scheele in 1784, is currently produced biotechnologically by fermentation of cane sugar or molasses by the Aspergillus niger mold. Citric acid is used in its natural form or as a food additive E 330 in the packaging of food, but also in baking powders, effervescent lemonades and generally for acidification and as a flavoring agent. It also serves
  • Citric acid to increase the stability of food or other organic substances.
  • the pure, anhydrous citric acid mostly forms colorless, rhombic crystals with a slightly acidic taste.
  • Effervescent formulations which contain creatine citrate as a 1: 1 salt or physical mixtures of creatine and citric acid are known from US Pat. No. 5,925,378.
  • the object of the present invention was to develop compounds consisting of creatine and citric acid which are particularly valuable physiologically, at the same time have good water solubility and adequate storage stability and can be prepared in a simple manner.
  • the creatine / citric acid compounds according to the invention have good storage stability, although the previously known salts of creatine easily decompose to form creatinine.
  • pure salts would be obtained. a. can be excluded by the IR bands as well as the presence of simple physical mixtures.
  • the addition and / or complex compounds according to the invention are particularly characterized in that they have a melting point which is between 110 and 160 ° C. and that they are generally free of organic Solvent proportions are contained, but a maximum of 0.1% by weight, which further increases the quality of the product properties.
  • the present invention takes into account that the addition and / or complex compounds consisting of creatine and citric acid are in a solid state, with powdery variants having proven to be particularly suitable.
  • Creatine and citric acid with a total water content of 5 to 15% by weight at temperatures between 0 and 70 ° C, in particular between 10 and 25 ° C, are mixed without solvents or dispersants and then by grinding in a mill, preferably in one Impact mill or other suitable grinding device;
  • citric acid component can also be used alternatively or additionally in the form of suitable citric acid salts.
  • the present invention also claims stable, physiologically tolerable formulations which contain the additive and / or complex compound consisting of creatine and citric acid, formulations being particularly preferred which contain further physiologically tolerable and / or physiologically active additives and / or contain formulation aids.
  • the present invention also includes the use of the additive and / or complex compound as a dietary supplement, feed additive, dietetic, in Functional Foods, for special nutrition, as well as for increasing endurance and strength in the sports area; but the compounds according to the invention can also be used for rehabilitation, as a neuroprotective agent, for improving wound healing, for myopathies and dystrophies and in the cosmetics sector, which also takes into account the invention.
  • Example 4 Production process for a creatine / citric acid compound of the composition creatine / citric acid in a molar ratio of 3: 1
  • the creatinine content was below the detection limit, ie below 100 pprn.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Fodder In General (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)

Abstract

The invention relates to addition and/or co-ordination compounds consisting of creatine and citric acid in the ratio of >1.0 to 3.0: 1.0. Said compounds are characterised in that they have (KBr) bands in the IR spectrum, where ξ= 3425 (± 5) cm-1 (s), 1624 (± 5) cm-1 (m-s) and 1247 (± 5) cm-1 (m). Said compounds, which preferably contain no organic solvent and are present in a solid, pulverulent form are produced in particular by a method, according to which, a¿1?) creatine, containing a maximum content of 20 wt. % water, is reacted with citric acid or its salts at temperatures between 0 and 70 °C, or a2) creatine and citric acid or its salts, containing a total water content of between 5 and 15 wt. %, are ground at temperatures between 0 and 70 °C, or a3) creatine is reacted with citric acid or its salts, in the presence of a solvent at temperatures between 0 and 70 °C. The corresponding solvent is then eliminated to a maximum residual content of 1.0 wt. %. The invention also relates to formulations that are suitable for use as food supplements, feed additives, dietetic agents, in functional foods, as neuroprotective agents, in addition to in the cosmetics industry etc.

Description

Kreatin/Citronensäure-Verbindung, Verfahren zu ihrer Herstellung und Verwendung Creatine / citric acid compound, process for its preparation and use
Die vorliegende Anmeldung betrifft Kreatin/Citronensäure- Verbindungen, deren Herstellung und geeignete Formulierungen sowie deren entsprechende Verwendung.The present application relates to creatine / citric acid compounds, their preparation and suitable formulations and their corresponding use.
Kreatin kommt vor allem im Muskel- und Nervengewebe vor und stellt in Form seines Stoff echselfolgeproduktes, dem Phosphokreatin, eine wichtige Energiereserve des Muskels und des Gehirns dar.Creatine is primarily found in muscle and nerve tissue and, in the form of its metabolic secondary product, phosphocreatine, is an important energy reserve for the muscle and brain.
Im Nerven- und Herzmuskelgewebe scheint Kreatin eine prophylaktische und therapeutische Wirkung bei Ischämien zu besitzen, wie sie z . B. durch Inf rktgeschehen oder durch prä- und perinatale Sauerstoffdefizit-Zustände verursacht werde .In nerve and cardiac muscle tissue, creatine appears to have a prophylactic and therapeutic effect in ischemia, such as that described in B. caused by inf rct events or by pre- and perinatal oxygen deficit conditions.
Kreatin ist seit über 100 Jahren als Muskelsubstanz bekannt, wobei es dem Muskel als Energiequelle dient.Creatine has been known as a muscle substance for over 100 years, and it serves as a source of energy for the muscle.
Kreatin stellt als körpereigene Substanz nicht nur ein wertvolles Nahrungsergänzungsmittel dar, sondern besitzt auch wertvolle therapeutische Eigenschaften. In einer Reihe von wissenschaftlichen Arbeiten wurde gezeigt, dass die kontrollierte Einnahme von Kreatin über einen längeren Zeitraum zu einer deutlichen Steigerung der Muskelmasse und Muskelleistung sowie der Kraft und Ausdauer führen kann.As a body's own substance, creatine is not only a valuable nutritional supplement, but also has valuable therapeutic properties. A number of scientific studies have shown that the controlled intake of creatine over a longer period of time can lead to a significant increase in muscle mass and muscle performance as well as strength and endurance.
Ein prophylaktischer, therapeutischer oder diätetischer Einsatz von Kreatin in den unterschiedlichsten Applikationsformen (z. B. oral, intravenös usw.) setzt eine hohe Bioverfügbarkeit und damit eine gute Wasserlöslichkeit voraus. Diese ist jedoch für Kreatin, das als Aminosäure- Derivat in Form eines inneren Salzes vorliegt, zumeist nicht in ausreichendem Maße gegeben, weshalb das Kreatin seine unbestrittenen Vorteile v. a.- im Rahmen von Supplementierungen und Therapien meist durch eines seiner physiologisch verträglichen Kreatin-Salze erzielt.The prophylactic, therapeutic or dietary use of creatine in a wide variety of application forms (e.g. oral, intravenous, etc.) requires high bioavailability and therefore good water solubility. However, this is usually not sufficient for creatine, which is present as an amino acid derivative in the form of an inner salt, which is why the creatine benefits from its undisputed advantages Supplements and therapies mostly achieved through one of its physiologically tolerable creatine salts.
Bei der Citronensäure handelt es sich um eine Tricarbonsäure, die bekanntermaßen im Pflanzenreich sowie in vielen tierischen Geweben und Körperflüssigkeiten verbreitet ist. Citronensäure zählt u. a. zur Reihe der prominenten Verbindungen, die bei der physiologischen Oxidation von Fetten, Eiweißen und Kohlenhydraten zu Kohlendioxid und Wasser mitwirken (vgl. u. a. Tricarbonsäure-Zyclus) .Citric acid is a tricarboxylic acid that is known to be common in the plant kingdom as well as in many animal tissues and body fluids. Citric acid counts u. a. to the series of prominent compounds that are involved in the physiological oxidation of fats, proteins and carbohydrates to carbon dioxide and water (see, inter alia, tricarboxylic acid cycle).
Citronensäure, die erstmals durch den schwedischen Chemiker Karl Wilhelm Scheele im Jahr 1784 aus Limonensaft isoliert worden ist, wird aktuell durch Fermentation von Rohrzucker oder Molasse durch den Schimmelpilz Aspergillus niger biotechnologisch hergestellt. Citronensäure wird in seiner natürlichen Form oder als Lebensmittelzusatzstoff E 330 bei der Konfektionierung von Lebensmitteln, aber auch in Backpulvern, Brauselimonaden und allgemein zur Ansäuerung sowie als Geschmacksstoff eingesetzt. Ferner dientCitric acid, which was first isolated from lime juice by the Swedish chemist Karl Wilhelm Scheele in 1784, is currently produced biotechnologically by fermentation of cane sugar or molasses by the Aspergillus niger mold. Citric acid is used in its natural form or as a food additive E 330 in the packaging of food, but also in baking powders, effervescent lemonades and generally for acidification and as a flavoring agent. It also serves
Citronensäure zur Erhöhung der Stabilität von Lebensmitteln oder anderen organischen Substanzen.Citric acid to increase the stability of food or other organic substances.
Die reine, wasserfreie Citronensäure bildet zumeist farblose, rhombische Kristalle mit leicht saurem Geschmack.The pure, anhydrous citric acid mostly forms colorless, rhombic crystals with a slightly acidic taste.
Aus dem US-Patent 5,973,199 sind u. a. isolierte, wasserlösliche Salze von Kreatin und Citronensäure bekannt, die einen Schmelzpunkt von 112 bis 114 °C aufweisen. Hergestellt wird dieses Kreatin-Citrat , indem Citronensäure- monohydrat in Ethylacetat suspendiert, dann Kreatin- monohydrat hinzugefügt und anschließend die Mischung für 4 Stunden bei 25 °C gemischt wird. Man erhält dadurch ein Produkt, das ca. 90 % an Kreatin-Citrat mit einem Schmelzpunkt zwischen 112 und 114 °C und variierende Lösemittelanteile enthält. Die US 6,211,407 (veröffentlicht am 3. April 2001) beschreibt Di- und Trikreatin-Citrate, deren Schmelzpunkte bei 146 bzw. 154°C liegen sollen und die einen Gehalt an Kreatin von 57,7 bzw. 67,2 Gew-% aufweisen. Angaben über die Struktur derartiger Salze bzw. Belege für deren Existenz sind der US 6,211,407 allerdings nicht zu entnehmen.From US Pat. No. 5,973,199, isolated, water-soluble salts of creatine and citric acid are known, which have a melting point of 112 to 114 ° C. This creatine citrate is produced by suspending citric acid monohydrate in ethyl acetate, then adding creatine monohydrate and then mixing the mixture for 4 hours at 25 ° C. This gives a product which contains about 90% of creatine citrate with a melting point between 112 and 114 ° C and varying proportions of solvents. US Pat. No. 6,211,407 (published April 3, 2001) describes di- and tricreatine citrates, the melting points of which should be 146 and 154 ° C. and which have a creatine content of 57.7 and 67.2% by weight. However, US 6,211,407 does not provide any information about the structure of such salts or evidence of their existence.
Brauseformulierungen, die Kreatincitrat als 1 : 1-Salz oder physikalische Mischungen aus Kreatin und Citronensäure enthalten, sind aus der Patentschrift US 5,925,378 bekannt.Effervescent formulations which contain creatine citrate as a 1: 1 salt or physical mixtures of creatine and citric acid are known from US Pat. No. 5,925,378.
Der vorliegenden Erfindung lag die Aufgabe zugrunde, Verbindungen bestehend aus Kreatin und Citronensäure zu entwickeln, die physiologisch besonders wertvoll sind, gleichzeitig eine gute Wasserlöslichkeit und eine ausreichende Lagerstabilität besitzen und in einfacher Weise herzustellen sind.The object of the present invention was to develop compounds consisting of creatine and citric acid which are particularly valuable physiologically, at the same time have good water solubility and adequate storage stability and can be prepared in a simple manner.
Gelöst wurde diese Aufgabe durch Anlagerungs- und/oder Komplexverbindungen, bestehend aus Kreatin und Citronensäure im Verhältnis > 1,0 bis 3,0 : 1,0, die durch ein IR-Spektrum (KBr) mit v = 3425 (+ 5) cm-1 (s) , 1624 (± 5) cm-1 (m-s) sowie 1247 (+ 5) cm-1 (m) gekennzeichnet sind.This problem was solved by addition and / or complex compounds consisting of creatine and citric acid in the ratio> 1.0 to 3.0: 1.0, which by an IR spectrum (KBr) with v = 3425 (+ 5) cm -1 (s), 1624 (± 5) cm -1 (ms) and 1247 (+ 5) cm -1 (m) are marked.
Überraschenderweise hat sich bei diesen Verbindungen gezeigt, dass die erfindungsgemäßen Kreatin/Citronensäure-Verbindungen eine gute Lagerstabilität aufweisen, obwohl sich die bislang bekannten Salze des Kreatins leicht unter Bildung von Kreatinin zersetzen. Zudem war davon auszugehen, dass man reine Salze erhält, was aber u. a. durch die IR-Banden ebenso ausgeschlossen werden kann wie das Vorliegen einfacher physikalischer Mischungen.Surprisingly, it has been found with these compounds that the creatine / citric acid compounds according to the invention have good storage stability, although the previously known salts of creatine easily decompose to form creatinine. In addition, it was to be assumed that pure salts would be obtained. a. can be excluded by the IR bands as well as the presence of simple physical mixtures.
Die erfindungsgemäßen Anlagerungs- und/oder Komplexverbindungen sind insbesondere dadurch gekennzeichnet, dass sie einen Schmelzpunkt aufweisen, der zwischen 110 und 160 °C liegt, und dass sie in der Regel frei von organischen Lösemittel-Anteilen sind, maximal jedoch davon 0,1 Gew.-% enthalten, was die Qualität der Produkteigenschaften zusätzlich erhöht.The addition and / or complex compounds according to the invention are particularly characterized in that they have a melting point which is between 110 and 160 ° C. and that they are generally free of organic Solvent proportions are contained, but a maximum of 0.1% by weight, which further increases the quality of the product properties.
Außerdem berücksichtigt die vorliegende Erfindung, dass die Anlagerungs- und/oder Komplexverbindungen bestehend aus Kreatin und Citronensäure in festem Zustand vorliegen, wobei sich pulverförmige Varianten als besonders geeignet erwiesen haben .In addition, the present invention takes into account that the addition and / or complex compounds consisting of creatine and citric acid are in a solid state, with powdery variants having proven to be particularly suitable.
Neben den Verbindungen selbst beansprucht die vorliegende Erfindung aber auch Verfahren zu deren Herstellung, wobei in drei alternativen ersten Schritten entwederIn addition to the compounds themselves, the present invention also claims processes for their preparation, in three alternative first steps either
a^) Kreatin mit einem Anteil von maximal 20 Gew.-% Wasser, insbesondere 10 bis 15 Gew.-% Wasser, bei Temperaturen zwischen 0 und 70 °C, insbesondere zwischen 10 und 25 °C, mit Citronensäure-monohydrat und/oder wasserfreier Citronensäure umgesetzt wird,a ^) Creatine with a maximum of 20 wt .-% water, in particular 10 to 15 wt .-% water, at temperatures between 0 and 70 ° C, in particular between 10 and 25 ° C, with citric acid monohydrate and / or anhydrous citric acid is implemented,
oderor
a2) Kreatin und Citronensäure mit einem Gesamtwassergehalt von 5 bis 15 Gew.-% bei Temperaturen zwischen 0 und 70 °C, insbesondere zwischen 10 und 25 °C, ohne Löseoder Dispergiermittel gemischt werden und dann durch eine Vermahlung in einer Mühle, vorzugsweise in einer Prallmühle oder einer sonstigen geeigneten Vermahleinrichtung, umgesetzt werden;a2) Creatine and citric acid with a total water content of 5 to 15% by weight at temperatures between 0 and 70 ° C, in particular between 10 and 25 ° C, are mixed without solvents or dispersants and then by grinding in a mill, preferably in one Impact mill or other suitable grinding device;
alternativ kann aber auchalternatively can also
33) Kreatin in wässriger oder alkoholischer Lösung oder in33) Creatine in aqueous or alcoholic solution or in
Gegenwart eines nicht mit Wasser mischbaren Lösemittels, vorzugsweise Ethylacetat, bei Temperaturen zwischen 0 und 70 °C mit Citronensäure-monohydrat und/oder wasserfreier Citronensäure umgesetzt werden. Dabei kann die Citronensäure-Komponente jeweils auch alternativ oder zusätzlich in Form geeigneter Citronensäure- Salze eingesetzt werden.In the presence of a water-immiscible solvent, preferably ethyl acetate, at temperatures between 0 and 70 ° C with citric acid monohydrate and / or anhydrous citric acid. The citric acid component can also be used alternatively or additionally in the form of suitable citric acid salts.
Im Anschluss an jede der drei genannten alternativen Verfahrensschritte a^) bis a3) wird im VerfahrensschrittFollowing each of the three alternative process steps a ^) to a3) mentioned in the process step
b) abschließend das Wasser oder Lösemittel, vorzugsweise unter Vakuum, auf einen Restgehalt von maximal 5 Gew.-% entfernt .b) finally the water or solvent, preferably under vacuum, is removed to a residual content of at most 5% by weight.
Selbstverständlich ist es mit all diesen Verfahrensvarianten ebenso möglich, neben den erfindungsgemäßen Verbindungen auch das 1 : 1-Salz des Kreatincitrats herzustellen.Of course, with all of these process variants it is also possible to produce the 1: 1 salt of creatine citrate in addition to the compounds according to the invention.
Neben den Verbindungen selbst sowie dem genannten Herstellungsverfahren beansprucht die vorliegende Erfindung auch stabile, physiologisch verträgliche Formulierungen, die die Anlagerungs- und/oder Komplexverbindung bestehend aus Kreatin und Citronensäure enthält, wobei Formulierungen besonders bevorzugt werden, die weitere physiologisch verträgliche und/oder physiologisch wirksame Zusätze und/oder Formulierungshilfsmittel enthalten .In addition to the compounds themselves and the production process mentioned, the present invention also claims stable, physiologically tolerable formulations which contain the additive and / or complex compound consisting of creatine and citric acid, formulations being particularly preferred which contain further physiologically tolerable and / or physiologically active additives and / or contain formulation aids.
Aus der Reihe der besonders geeigneten physiologisch verträglichen und/oder physiologisch wirksamen Zusätze haben sich insbesondere Zucker, Alkohole, Vitamine, Spurenelemente, Aminosäure, Neurotransmitter, Stimulantien sowie Färb- und Aromastoffe als geeignet erwiesen. Kohlenhydrate, wie z. B. Methylcellulosen, SiÜ2, Lösevermittler, Aromastoffe, sowie Stearate und andere Trenn- und Konservierungsmittel und Texturantien werden als Formulierungshilfsmittel bevorzugt.From the series of particularly suitable physiologically compatible and / or physiologically active additives, sugar, alcohols, vitamins, trace elements, amino acids, neurotransmitters, stimulants as well as coloring and flavoring substances have proven to be particularly suitable. Carbohydrates such as B. methyl celluloses, SiÜ2, solubilizers, flavorings, as well as stearates and other release agents and preservatives and texturants are preferred as formulation aids.
Schließlich umfasst die vorliegende Erfindung auch noch die Verwendung der Anlagerungs- und/oder Komplexverbindung als Nahrungsergänzungsmittel, Futterzusatzmittel, Diätetikum, in Functional Foods, zur Sonderernährung, sowie zur Steigerung der Ausdauer und Kraft im Sportbereich; aber auch zur Rehabilitation, als Neuroprotektivum, zur Verbesserung der Wundheilung, bei Myopathien und Dystrophien sowie im Kosmetikbereich können die erfindungsgemäßen Verbindungen eingesetzt werden, was die Erfindung ebenfalls berücksichtigt .Finally, the present invention also includes the use of the additive and / or complex compound as a dietary supplement, feed additive, dietetic, in Functional Foods, for special nutrition, as well as for increasing endurance and strength in the sports area; but the compounds according to the invention can also be used for rehabilitation, as a neuroprotective agent, for improving wound healing, for myopathies and dystrophies and in the cosmetics sector, which also takes into account the invention.
Mit den vorrangig beanspruchten Anlagerungs- und/oder Komplexverbindungen,_ bestehend aus Kreatin und Citronensäure, erhält man ein qualitativ hochstehendes Produkt, das i. d. R. weitgehend frei von organischen Lösemitteln ist, das aufgrund seines geringen Wassergehaltes äußerst lagerstabil ist und . das trotz seines nicht salzartigen Charakters dennoch wertvolle physiologische Eigenschaften besitzt.With the additive and / or complex compounds, consisting primarily of creatine and citric acid, you get a high quality product that i. d. R. is largely free of organic solvents, which is extremely stable due to its low water content and. which, despite its non-salt character, still has valuable physiological properties.
Die nachfolgenden Beispiele verdeutlichen diese Vorteile der erfindungsgemäßen Anlagerungs- und/oder Komplexverbindung.The following examples illustrate these advantages of the addition and / or complex compound according to the invention.
BeispieleExamples
Beispiel 1example 1
Herstellungsverfahren für eine Kreatin/Citronensäure- Verbindung der Zusammensetzung Kreatin/Citronensäure im Molverhältnis 3 : 1Production process for a creatine / citric acid compound of the composition creatine / citric acid in a molar ratio of 3: 1
448 kg (3 mol) Kreatin-Monohydrat und 4,5 kg (0,03 mol) Wasser wurden in einem Trockner vorgelegt und eine halbe Stunde gemischt. Darauf gab man 210 kg (1 mol) Citronensäure- Monohydrat dazu. Nach einer Stunde wurde die448 kg (3 mol) of creatine monohydrate and 4.5 kg (0.03 mol) of water were placed in a dryer and mixed for half an hour. Then 210 kg (1 mol) of citric acid monohydrate were added. After an hour the
Reaktionsmischung unter Vakuum eine weitere Stunde gemischt. Zum Trocknen wurde die Temperatur durch dosierte Wärmezufuhr bis maximal 60 °C erhöht. Auf diese Weise erhielt man ca. 593 kg (> 99 %) einer Kreatin/Citronensäure-Zusammensetzung mit einem Restfeuchte-Gehalt von 0,04 Gew-% (gem. Karl- Fischer-Methode) . Schmelzpunkt: 148-152 °C;Reaction mixture mixed under vacuum for another hour. For drying, the temperature was raised to a maximum of 60 ° C by metered heat supply. In this way, about 593 kg (> 99%) of a creatine / citric acid composition with a residual moisture content of 0.04% by weight (according to the Karl Fischer method) were obtained. Melting point: 148-152 ° C;
IR (KBr) : v = 3425 cm-1 (s) , 1663 (s) , 1624 (s) , 1247 (m) .IR (KBr): v = 3425 cm -1 (s), 1663 (s), 1624 (s), 1247 (m).
Beispiel 2Example 2
Herstellungsverfahren für eine Kreatin/Citronensäure- Verbindung der Zusammensetzung Kreatin/Citronensäure im Molverhältnis 2 : 1Production process for a creatine / citric acid compound of the composition creatine / citric acid in a molar ratio of 2: 1
Aus feuchtem Kreatin (ca. 20 - 25 % Wasser), welches aus dem Herstellungsprozess von Kreatin-Monohydrat gemäß EP-B 754 679 stammte, erhielt man durch Trocknung bis zu einem Restgehalt von 14 % Wasser 301 kg (2 mol) feuchtes Kreatin. Darauf gab. man 210 kg (1 mol) Citronensäure-Monohydrat hinzu. Nach einer Stunde wurde die Mischung unter Vakuum eine weitere Stunde gemischt. Zum Trocknen wurde die Temperatur durch Wärmezufuhr bis maximal 60 °C erhöht. Auf diese Weise erhielt man ca. 457 kg (> 99 %) einer Kreatin/Citronensäure-Zusammensetzung mit einem Restfeuchte-Gehalt von 0,07 Gew-% (gem. Karl- Fischer-Methode) .From moist creatine (approx. 20 - 25% water), which originated from the production process of creatine monohydrate according to EP-B 754 679, 301 kg (2 mol) of moist creatine were obtained by drying to a residual content of 14% water. Thereupon gave. 210 kg (1 mol) of citric acid monohydrate are added. After one hour the mixture was mixed under vacuum for an additional hour. For drying, the temperature was raised to a maximum of 60 ° C. by applying heat. In this way, about 457 kg (> 99%) of a creatine / citric acid composition with a residual moisture content of 0.07% by weight (according to the Karl Fischer method) were obtained.
Schmelzpunkt: 145 - 150 °C;Melting point: 145-150 ° C;
IR (KBr): v = 3425 cm-1 (s) , 1669 (m) , 1624 (s) , 1247 (m) .IR (KBr): v = 3425 cm -1 (s), 1669 (m), 1624 (s), 1247 (m).
Beispiel 3Example 3
Herstellungsverfahren für eine Kreatin/Citronensäure- Verbindung der Zusammensetzung Kreatin/Citronensäure im Molverhältnis 1,5 : 1Production process for a creatine / citric acid compound of the composition creatine / citric acid in a molar ratio of 1.5: 1
2,24 kg (0,015 mol) Kreatin-monohydrat und 2,10 kg (0,01 mol) Citronensäure-Monohydrat wurden bei Raumtemperatur gemischt und anschließend in einer Prallmühle (99 % < 150 μm) durch Vermahlung umgesetzt. Darauf wurde das Produkt getrocknet. Auf diese Weise erhielt man ca. 3,92 kg (> 99 %) einer Kreatin/Citronensäure-Zusammensetzung mit einem Restfeuchte- Gehalt von 0,06 Gew-% (gem. Karl-Fischer-Methode). Schmelzpunkt: 130 - 138 °C;2.24 kg (0.015 mol) of creatine monohydrate and 2.10 kg (0.01 mol) of citric acid monohydrate were mixed at room temperature and then reacted in an impact mill (99% <150 μm) by grinding. The product was then dried. In this way, about 3.92 kg (> 99%) of a creatine / citric acid composition with a residual moisture content of 0.06% by weight (according to the Karl Fischer method) was obtained. Melting point: 130-138 ° C;
IR (KBr) : v = 3428 cm"1 (s) , 1700 (m) , 1619 (s) 1247 (m) .IR (KBr): v = 3428 cm " 1 (s), 1700 (m), 1619 (s) 1247 (m).
Beispiel 4 Herstellungsverfahren für eine Kreatin/Citronensäure- Verbindung der Zusammensetzung Kreatin/Citronensäure im Molverhältnis 3 : 1Example 4 Production process for a creatine / citric acid compound of the composition creatine / citric acid in a molar ratio of 3: 1
448 kg (3 mol) Kreatin-Monohydrat und 500 kg Ethanol wurden in einem Trockner vorgelegt und eine halbe Stunde gemischt.448 kg (3 mol) of creatine monohydrate and 500 kg of ethanol were placed in a dryer and mixed for half an hour.
Darauf gab man 210 kg (1 mol) Citronensäure-Monohydrat hinzu. Nach vier Stunden wurde die Reaktionsmischung unter Vakuum eine weitere Stunde gemischt . Zum Trocknen wurde die Temperatur durch dosierte Wärmezufuhr bis maximal 60 °C erhöht. Auf diese Weise erhielt man ca. 593 kg (> 99 %) einer Kreatin/Citronensäure-Zusammensetzung mit einem Restgehalt an Ethanol von 0,1 Gew-% (gaschromatographisch) .Then 210 kg (1 mol) of citric acid monohydrate were added. After four hours the reaction mixture was mixed under vacuum for an additional hour. For drying, the temperature was raised to a maximum of 60 ° C by metered heat supply. In this way, about 593 kg (> 99%) of a creatine / citric acid composition with a residual ethanol content of 0.1% by weight (gas chromatography) were obtained.
Schmelzpunkt: 148 - 152 °C; IR (KBr) : V = 3425 cm-1 (s) , 1663 (s) , 1624 (s) , 1247 (m) .Melting point: 148-152 ° C; IR (KBr): V = 3425 cm -1 (s), 1663 (s), 1624 (s), 1247 (m).
Bei allen vier genannten Erfindungsbeispielen lag der Kreatinin-Gehalt jeweils unter der Nachweisgrenze, also unter 100 pprn. In all four examples of the invention mentioned, the creatinine content was below the detection limit, ie below 100 pprn.

Claims

Patentansprüche claims
1. Anlagerungs- und/oder Komplexverbindung bestehend aus Kreatin und Citronensäure im Verhältnis > 1,0 bis 3,0 : 1,0, gekennzeichnet durch ein IR-Spektrum (KBr) v = 3425 (± 5) cm-1 (s) , 1624 (+ 5) cm-1 (m-s), 1247 (+ 5) cm-1 (m) .1. Addition and / or complex compound consisting of creatine and citric acid in a ratio> 1.0 to 3.0: 1.0, characterized by an IR spectrum (KBr) v = 3425 (± 5) cm -1 (s) , 1624 (+ 5) cm -1 (ms), 1247 (+ 5) cm -1 (m).
2. Verbindung nach Anspruch 1, dadurch gekennzeichnet, dass sie einen Schmelzpunkt von 110 bis 160 °C aufweist.2. A compound according to claim 1, characterized in that it has a melting point of 110 to 160 ° C.
3. Verbindung nach einem der Ansprüche 1 oder 2 , dadurch gekennzeichnet, dass sie maximal 0,1 Gew.-% an organischem Lösemittel enthält .3. Compound according to one of claims 1 or 2, characterized in that it contains a maximum of 0.1 wt .-% of organic solvent.
4. Verbindung nach einem der Ansprüche 1 bis 3 , dadurch gekennzeichnet, dass sie in festem, vorzugsweise pulverförmigem, Zustand vorliegt.4. Connection according to one of claims 1 to 3, characterized in that it is in a solid, preferably powdery, state.
5. Verfahren zur Herstellung der Verbindung nach einem der5. Process for the preparation of the compound according to one of the
Ansprüche 1 bis 4, dadurch gekennzeichnet, dassClaims 1 to 4, characterized in that
a^_) Kreatin mit einem Anteil von maximal 20 Gew.-%a ^ _) creatine with a maximum of 20% by weight
Wasser, insbesondere 10 bis 15 Gew.-% Wasser, bei Temperaturen zwischen 0 und 70 °C, insbesondere zwischen 10 und 25 °C, mit Citronensäure-monohydrat und/oder wasserfreier Citronensäure und/oder deren geeignete Salze umgesetzt wird,Water, in particular 10 to 15% by weight of water, at temperatures between 0 and 70 ° C., in particular between 10 and 25 ° C., is reacted with citric acid monohydrate and / or anhydrous citric acid and / or their suitable salts,
oderor
a2 ) Kreatin und Citronensäure und/oder deren geeignete Salze mit einem Gesamtwassergehalt von 5 bis 15 Gew . -% bei Temperaturen zwischen 0 und 70 °C, insbesondere zwischen 10 und 25 °C, ohne Löse- odera2) creatine and citric acid and / or their suitable salts with a total water content of 5 to 15 wt. -% at temperatures between 0 and 70 ° C, in particular between 10 and 25 ° C, without dissolving or
Dispergiermittel gemischt werden und dann durch eine Vermahlung in einer Mühle, vorzugsweise in einer Prallmühle, umgesetzt werden,Dispersants are mixed and then through grinding in a mill, preferably in an impact mill, is implemented,
oderor
33) Kreatin in wässriger oder alkoholischer Lösung oder in Gegenwart eines nicht mit Wasser mischbaren Lösemittels, vorzugsweise Ethylacetat, bei Temperaturen zwischen 0 und 70 °C mit Citronensäure-monohydrat und/oder wasserfreier33) Creatine in aqueous or alcoholic solution or in the presence of a water-immiscible solvent, preferably ethyl acetate, at temperatures between 0 and 70 ° C with citric acid monohydrate and / or anhydrous
Citronensäure und/oder deren geeignete Salze umgesetzt wird, undCitric acid and / or its suitable salts is implemented, and
b) abschließend das Wasser oder Lösemittel, vorzugsweise unter Vakuum, auf einen Restgehalt von maximal 5 Gew.-% entfernt wird.b) finally the water or solvent, preferably under vacuum, is removed to a residual content of at most 5% by weight.
6. Formulierung enthaltend die Verbindung nach einem der Ansprüche 1 bis 4.6. Formulation containing the compound according to one of claims 1 to 4.
7. Formulierung nach Anspruch 6, dadurch gekennzeichnet, dass sie weitere physiologisch verträgliche und/oder physiologisch wirksame Zusätze und/oder Formulierungshilfsmittel enthält.7. Formulation according to claim 6, characterized in that it contains further physiologically compatible and / or physiologically active additives and / or formulation auxiliaries.
8. Formulierung nach einem der Ansprüche 6 oder 7, dadurch gekennzeichnet, dass sie als physiologisch verträgliche und/oder physiologisch wirksame Zusätze Zucker, Alkohole, Vitamine, Spurenelemente, Aminosäure,8. Formulation according to one of claims 6 or 7, characterized in that it contains, as physiologically compatible and / or physiologically active additives, sugars, alcohols, vitamins, trace elements, amino acids,
Neurotransmitter, Stimulantien, Färb- und Aromastoffe enthält .Contains neurotransmitters, stimulants, colorants and flavorings.
9. Formulierung nach einem der Ansprüche 6 bis 8, dadurch gekennzeichnet, dass sie als Formulierungshilfsmittel9. Formulation according to one of claims 6 to 8, characterized in that it is used as a formulation aid
Kohlenhydrate, Siθ2, Stearate, Lösevermittler, Aromastoffe, Konservierungs- und Trennmittel sowie Texturantien enthält.Carbohydrates, SiO 2, stearates, solubilizers, Contains flavorings, preservatives and release agents as well as texturants.
10. Verwendung der Verbindung nach den Ansprüchen 1 bis 4 als Nahrungsergänzungs ittel, Futterzusatzmittel,10. Use of the compound according to claims 1 to 4 as a food supplement, feed additive,
Diatetikum, in Functional Foods, zur Sonderernährung, zur Steigerung der Ausdauer und Kraft im Sportbereich, zur Rehabilitation, als Neuroprotektivum, zur Verbesserung der Wundheilung, bei Myopathien und Dystrophien sowie im Kosmetikbereich. Diatetic, in functional foods, for special nutrition, to increase endurance and strength in the sports sector, for rehabilitation, as a neuroprotective agent, to improve wound healing, for myopathies and dystrophies and in the cosmetics sector.
EP01272630A 2000-12-28 2001-11-16 Creatine/citric acid compound, method for the production of the same and the use thereof Withdrawn EP1345502A1 (en)

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