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• • 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
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/17—Amino acids, peptides or proteins
  • A23L33/18—Peptides; Protein hydrolysates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • 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

• Solid or aqueous alkaline preparation comprising a creatine component, process for its preparation and its use
• the present invention is a solid or aqueous alkaline preparation comprising a creatine component, processes for their preparation and their use as dietary supplements, tonics, medicinal preparations and feed.
• Creatine monohydrate is today the most important nutritional supplement in the sports sector.
• creatine has antioxidant and neuroprotective properties and thus can also be used to prevent damage to the cells by environmental influences (Sestili, Piero et al .: Creatine supplementation cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity Radical Biology & Medicine (2006), 40 (5), 837-849; P. Klivenyi et al .: Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis, Nature Medicine 5, 347-350 (1999)). Therefore, creatine will become increasingly important in the anti-aging field in the future as well.
• creatine The positive effects of creatine are currently being studied extensively in the medical field, with creatine being in Phase 3 clinical trials for Parkinson's and Amyotrophic Lateral Sclerosis (ALS) and Phase 2 in Corea Huntington's (EP 804 183 B1). , Also against a successful use of creatine as a therapeutic against Asthma has already been reported (EP 911 026 B1). When building bones, creatine showed positive effects both in vitro and in vivo.
• creatine supplementation leads to an increase in body mass. This is initially due to an increased intake of water in the muscle. In the long term, however, creatine indirectly leads to an increase in muscle mass due to increased protein synthesis or reduced protein catabolism in the myofibrils (Int J Sports Med 21 (2000), 139-145). The result is thus an increased fat-free body mass.
• creatine In addition to the creatine itself, ie creatine monohydrate, numerous creatine salts, such as creatine ascorbate, citrate, pyruvate, phosphate and others, have also proved to be suitable dietary supplements. Representative may be mentioned at this point the European patent EP 894 083 and the German patent application DE 197 07 694 A1 as prior art.
• the metabolism and mode of action of creatine are very well studied.
• the biosynthesis starts from glycine and L-arginine.
• the guanidino group of L-arginine is cleaved by the enzyme aminotransferase and transferred an NCN group to the glycine.
• the L-arginine is converted into L-ornithine. The way - A -
• guanidinoacetic acid formed in the next step which occurs in vertebrates especially in the liver, using the enzyme transmutase converted into creatine.
• the S-adenosylmethionine serves as a methyl group donor.
• the creatine then diffuses into the bloodstream and is thus transported to the target organs.
• the transport through the cell membrane into the cells takes place here through a specific NaCI-dependent creatine transporter (Speer O, Neukomm LJ 1 Murphy RM, Zanolla E, Schlattner U, Henry H, Snow RJ, Wallimann T. Creatine transporters: a reappraisal. Mol Cell Biochem., 2004 Jan-Feb; 256-257 (1-2): 407-24).
• Creatine plays an important role in the energy metabolism of the cell, being a high-energy phosphocreatine in addition to the adenosine triphosphate (ATP) represents an essential energy reserve of the muscle.
• ATP adenosine triphosphate
• Creatine plays an essential energy reserve of the muscle.
• ATP can transfer a phosphate group to creatine, forming phosphocreatine, which is then in direct equilibrium with ATP.
• the phosphocreatine is available in the first few seconds of maximum muscle load.
• the enzyme creatine kinase can transfer a phosphate group to adenosine diphosphate and thus rebuild ATP. This is also called Lohmann reaction.
• creatine has an important function in the transmission of energy in the cell.
• the so-called creatine shuttle system transports energy from the mitochondria to the places in the cell where the energy is needed.
• creatine stores in the body are quickly exhausted. For this reason, especially in competitive athletes targeted creatine gifts have a positive effect on endurance and performance, with unwanted enrichment processes in the body or adverse Degradation products are unknown.
• the reason for this is that creatine is excreted from the body through the kidneys when it is over-supplied. Furthermore, creatine is converted at a constant rate into the cyclic by-product creatinine, which is also excreted by the kidneys and thus constitutes a second metabolic pathway.
• the uptake of creatine into the muscles is controlled by a NaCI-dependent creatine transporter and can be positively influenced by the simultaneous intake of carbohydrates and proteins. It showed that the combination of creatine and carbohydrates compared to the sole intake of creatine can lead to a 60% increase in the creatine content in muscle (Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL carbohydrates ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans., J J Physiol, 1996 Nov; 271 (5 Pt 1): E821-6). It has been shown that the secretion of insulin plays an important role in the uptake of creatine into muscle cells.
• Creatine In addition to its undisputed positive physiological properties, creatine also has the disadvantage that it has no pronounced stability in the corresponding aqueous solutions. Creatine cyclizes through the elimination of water to creatinine. The rate of cyclization depends on the pH of the solution and the temperature, the concentration being irrelevant. Especially in the neutral and acidic pH range, the conversion into creatinine is very fast. Due to the rapid breakdown of creatine in this environment, the use in aqueous or moist formulations for human and animal nutrition is practically impossible. Already the pH of the Depending on the residence time, stomach 1 to 2 can lead to a significant breakdown of creatine to creatinine. (Greenhaff, PL: Factors Modifying Creatine Accumulation in Human Skeletal Muscle.) In: Creatine., From Basic Science to Clinical Application, Medical Science Symposia, Volume 14, 2000, 75-82).
• EP 669 083 A2 claims an alkaline creatine drink and its preparation, which is characterized by the stability of the creatine during the preservation process.
• the scope of protection also extends to a process in which 1.) water is introduced and heated with a basic pH, 2.) 1-3 g of creatine are dissolved per 100 ml with stirring and 3.) additives for increasing the nutrient content and Improvement of the taste can be added.
• a special base for adjusting the pH is not described in this application.
• US 6,399,661 claims a creatine preparation intended to serve the nutritional purpose.
• the claimed preparation proceeds via a three-step process in which 1.) an alkaline powder is mixed with powdered creatine to obtain a mixture of pH 7 to 14; 2.) adding a powdery additive to improve the sweetness and taste of the mixture; and 3.) adding another alkaline powder to adjust the pH of the mixture to values between 7 and 14.
• the base used is preferably sodium carbonate and / or magnesium glycerol phosphate.
• the alkaline component from the group of hydroxides, carbonates, Bicarbonates, chlorides, tree latex or phosphates.
• EP 1 520 580 A1 claims a method for increasing endurance in mammals and humans by using a creatine preparation which has a pH between 7 and 14.
• the formulations used correspond to the mixtures described in US Pat. No. 6,399,661.
• Creatine preparations chosen. These are initially stable after dissolution in water, after oral intake, such a dose due to the small amount of base contained very quickly by the
• Gastric acid is adjusted to an acidic pH and creatine becomes unstable.
• the object of the present invention has been to develop formulations that better the creatine before the
• Creatinine is formed, which is useless for the body and thus must be eliminated via the kidneys from the body.
• a preparation comprising a creatine component, wherein the preparation in addition to the creatine component contains a buffer system that sets a pH of 8.0 to 12.0.
• the preparation is an alkaline preparation, which is particularly preferably solid or aqueous.
• the preparation according to the present invention consists of a creatine component and a buffer system, wherein the buffer system is a combination of a weak acid and the corresponding base.
• the creatine component used is preferably creatine, creatine monohydrate and / or at least one salt and an attachment or complex compound thereof.
• the at least one salt which comprises at least one addition and / or complex compound selected from the group consisting of malic acid, ascorbic acid, succinic acid, pyruvic acid, fumaric acid, aspartic acid, gluconic acid, ⁇ -ketoglutaric acid, oxalic acid, pyroglutamic acid, 3-nicotinic, maleic, sulfuric, acetic, formic, phosphoric, hydrochloric, 2-hydroxybenzoic, ⁇ -lipoic, L-carnitine, acetyl-L-carnitine, taurine, betaine, choline and methionine.
• the creatine component is solid, especially as a powder or in aqueous solution.
• the buffer system sets a pH of 8.0 to 12.0 and preferably 10.0 to 11.0.
• the present invention provides a mixture of sodium carbonate and sodium bicarbonate.
• the ratio of the two components can be freely selected within wide limits, this being preferably chosen so that the pH of the formulation is adjusted to 10.0 to 11.0. In this case, it is advantageous that, given the correct choice of the mixing ratio, the amount used is practically not restricted. Thus, when using a 1 to 1 mixture inevitably a pH of 10.4, wherein this is independent of the total amount of buffer used.
• an organoleptically acceptable pH can be adjusted and, at the same time, the creatine is optimally protected from the influence of acid, thereby avoiding conversion to creatinine.
• Also suitable as further buffer systems are mixtures of sodium hydrogen phosphate and sodium phosphate or L-lysine and L-lysine sodium salt or L-arginine and L-arginine sodium salt, the ratio used in turn being chosen so that the pH of the formulation preferably to 10.0 to 11, 0 sets.
• the formulation is not limited with respect to the buffer component, wherein in particular the amount of the buffer component in which it can be present in the preparation is not limiting.
• amounts are recommended which are between 0.1 and 90.0 wt .-%, based on the total weight of the preparation. Particular preference is given to amounts between 2.5 and 15.0% by weight and in particular 5.0 to 10.0% by weight, based on the total weight of the preparation.
• the present invention thus also provides, in addition to the buffer system, optionally incorporation of one or more further physiologically acceptable sodium salts or a mixture thereof into the preparations according to the invention.
• sodium chloride, sodium sulfate, sodium acetate, sodium citrate, sodium gluconate, sodium ascorbate, sodium pantothenate and sodium lactate or mixtures of these salts are suitable for this purpose.
• these sodium salts is relatively uncritical, but it has proved to be particularly advantageous, these other sodium salts in an amount of 0.1 to 75.0 wt .-%, in particular 5.0 to 55.0 wt .-% and especially preferably 10.0 to 20.0 wt .-%, based on the total weight dero preparation to use.
• the preparation according to the invention contains further physiologically active compounds, such as. As carbohydrates, fats, amino acids, proteins, vitamins, minerals, trace elements and derivatives and mixtures thereof.
• physiologically active compounds such as. As carbohydrates, fats, amino acids, proteins, vitamins, minerals, trace elements and derivatives and mixtures thereof.
• ⁇ -lipoic acid and / or guanidinoacetic acid it is also possible to add ⁇ -lipoic acid and / or guanidinoacetic acid to the preparation according to the invention for improving the bioavailability.
• the solids content is preferably set to 0.01 to 14.0 wt .-%.
• Another object of the present invention is a process for the preparation of the preparation according to the invention, wherein the creatine component is introduced, a buffer system, preferably a mixture of a weak acid and the corresponding base is incorporated and optionally further sodium salts, physiologically active compounds and / or ⁇ -lipoic acid and / or guanidinoacetic acid are added.
• a buffer system preferably a mixture of a weak acid and the corresponding base is incorporated and optionally further sodium salts, physiologically active compounds and / or ⁇ -lipoic acid and / or guanidinoacetic acid are added.
• the creatine component is presented as a powder or aqueous solution.
• the buffer system is preferably incorporated homogeneously.
• a preferred aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising the preparation according to the invention and optionally one or more pharmaceutically acceptable carriers and / or adjuvants.
• the present invention further claims the use of the preparation according to the invention as a dietary supplement.
• the use of the claimed preparation as a physiological restorative and, in this context, in particular in the form of a functional food for humans, is taken into account, the school, sports, convalescence and / or geriatrics area are in the foreground.
• the described positive effects develop the described formulations also in animals, so that the use is also provided in this area.
• the described creatine formulations are used as a feed additive, the administration to breeding and fattening animals as well as to animals in competitive sport is to be considered as preferred and in this context particularly preferred to pigs, horses, poultry and fish, whereby the use as substitute for animal and / or fish meal and products made therefrom has proven to be particularly suitable.
• the replacement can take place as a partial or full replacement.
• the new creatine preparation can also be used as a dietary supplement or nutritional ingredient for pets such as dogs, cats and birds.
• Powder, granules, lozenges, capsules, tablets, solutions, juices and / or jelly products have proven particularly suitable as application forms. Depending on the specific case of use, it may well be advisable to use the preparation according to the invention in combination with other physiologically active substances.
• the preparation according to the invention can be administered in single doses of 0.001 to 0.3 g / kg of body weight or in daily doses of between 0.001 and 1.0 g / kg of body weight.
• compositions of neutral or savory formulations the ingredients of which are incorporated at room temperature in 500 ml of fruit juice, water, yogurt and / or whey.
• Creatine monohydrate and Kre-Alkalyn ® and an inventive creatine preparation according to example 1.1 were dissolved in 500 ml of water. The amount was always chosen so that in each solution 2980 mg of creatine monohydrate was introduced. It was then titrated with 0.1 molar hydrochloric acid, wherein the pH curve was measured with a pH electrode.
• the formulation according to the invention tolerated a significantly greater addition of acid before it turned into the acidic region, as can be clearly seen from FIG.

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• 2006
  • 2006-10-28 DE DE102006050931A patent/DE102006050931A1/de not_active Ceased
• 2007
  • 2007-10-26 EP EP07819368A patent/EP2094116B1/de active Active
  • 2007-10-26 DE DE502007003888T patent/DE502007003888D1/de active Active
  • 2007-10-26 ES ES07819368T patent/ES2341910T3/es active Active
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  • 2007-10-26 US US12/312,158 patent/US20100056633A1/en not_active Abandoned
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  • 2007-10-26 WO PCT/EP2007/009324 patent/WO2008052712A1/de not_active Ceased
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