Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
  • A61K36/483—Gleditsia (locust)
• • 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
  • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
  • A23L2/385—Concentrates of non-alcoholic beverages
  • A23L2/39—Dry compositions
• • 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
  • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
  • A23L2/52—Adding ingredients
• • 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
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • 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
  • A23L33/175—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
  • 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
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/88—Liliopsida (monocotyledons)
  • A61K36/886—Aloeaceae (Aloe family), e.g. aloe vera
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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

• This invention relates to compositions for human consumption comprising creatine and creatinine and to a method of providing stable creatine containing compositions.
• Creatine plays a pivotal role in the regulation and homeostasis of skeletal muscle energy metabolism and it is now generally accepted that the maintenance of phospho-creatine availability is important to the continuation of muscle force production. Creatine may also be involved in other processes concerned with protein synthesis and hypertrophy of muscle fibres during training.
• creatine synthesis occurs in the liver, kidney and pancreas it has been known for sometime that the oral ingestion of creatine will add to the whole body creatine pool, and it has been shown that the ingestion of 20 to 30g creatine monohydrate (Cr.H 2 O) per day for several days can lead to a greater than 20% increase in human skeletal muscle total creatine content.
• WO94/02127 discloses the administration of creatine monohydrate in amounts of at least 15g (or 0.2-0.4 g/kg body weight) per day, for at least 2 days, for increasing muscular strength.
• Aloe Vera (Aloe barbadensis) is a member of the lily family and is a cactus-like succulent plant that grows in warm frost-free climates. Central American Mexican Indians used Aloe Vera for centuries as a remedy for burns, to prevent blisters, peptic and duodenal ulcers and all types of stomach and intestinal disorders, kidney infections, topical and gastric ulcers as well as to promote longevity. Today Aloe Nera is becoming very popular and its benefits are scientifically recognized.
• Aloe Vera The main use of Aloe Vera in the past has been to prevent inflammation, particularly to the skin, especially after burns, but there are many other uses. Experiments and research studies have shown that after using Aloe Vera juice, the output of the digestive enzymes and the bacterial population of the intestines are improved. Thus there has been an increasing interest in Aloe Vera extract as a medicament to be taken orally as people become more acquainted with its medicinal properties
• Aloe Vera juice is acidic (commonly about pH 3). It is well known that the creatine molecule is unstable in aqueous solutions at acid or neutral pH, and is converted into the related compound creatinine. This is highly significant as creatinine has no muscle performance-enhancing effect and is excreted from the human body as a waste product in urine.
• EP 0 669 083 teaches that aqueous drinks for human consumption comprising creatine must be weakly alkaline, in order to limit the conversion of creatine into creatinine, and this has become the generally accepted opinion.
• creatine and its derivatives have been used in the past but only for the preparation of products with a meaty or savory flavor.
• Tonsbeek (US 3,615,600) discloses and is concerned with artificial flavoring, describing mixtures imparting a meaty flavor to foods.
• Similary de Rooji (US 4, 464, 409) is concerned with meat flavoring.
• Yamazaki (JP-A-59035663) prepares a meat flavor by heating a mixture comprising creatine at pH 5.0-7.0 at a temperature of 80-130°C for 30 - 120 minutes. Under these conditions most of the creatine is converted to creatinine.
• WO 97/45026 discloses an acidic composition for human consumption comprising creatine and its derivatives, the composition being provided as a dry powder or in liquid or semi-liquid form.
• the compositions disclosed therein are stable at refrigerated temperatures (4°C) for prolonged periods but stable at ambient temperature for relatively short periods (e.g. up to, but not exceeding, 7 days).
• WO 00/74500 discloses compositions comprising creatine and its derivatives suspended in aloe vera gel, which compositions were stable (with respect to the conversion of creatine to creatinine) at room temperature for 2 weeks or more, depending on the initial concentration of creatine in the composition.
• the present invention is concerned with the provision of compositions for human consumption comprising creatine and its derivatives, especially compositions presented in an aqueous medium, more especially compositions (such as drinks) in which creatine is provided in aqueous solution or in which creatine is suspended in an edible supporting matrix.
• creatine as used herein is intended to encompass all bioavailable derivatives of creatine, such as creatine monohydrate, phosphocreatine, and other salts of creatine. Creatine monohydrate is particularly preferred. Accordingly the term “creatine” should be construed broadly where the context permits.
• the invention provides a composition for human consumption comprising creatine and a quantity of creatinine sufficient to render the creatine therein substantially stable (as defined below) in an aqueous medium.
• the creatinine content of the composition is present ab initio, (i.e. upon formation of the final composition), rather than arising during the storage of the composition as a result of the conversion of creatine into creatinine.
• the production of the composition i.e. processing prior to formation of the final compositions
• Stability of the creatine ab initio is desirable commercially, because it allows exact characterisation of the creatine content of the composition (which may, for example, be indicated on packaging and the like) and it allows consumers to calculate the exact dose of creatine consumed.
• the composition may be provided as a liquid, a semi-liquid, an edible matrix or a solid for subsequent solution in water.
• the creatine can be dissolved in water to provide a liquid.
• the creatine content for the composition is preferably subjected to a micronisation process (e.g. crushing, pulverising, powdering and the like) prior to incorporation into a semi-liquid or other supporting matrix so that the resulting composition is not unacceptably gritty in texture.
• a micronisation process e.g. crushing, pulverising, powdering and the like
• the supporting matrix is a recognised foodstuff, such that a composition in accordance with the invention may take the form of an otherwise conventional foodstuff, supplemented with creatine and creatinine, such that solid creatine becomes suspended in the foodstuff.
• foodstuffs which may represent suitable supporting matrices for the composition of the invention include spreadable solids such as dairy or cheese spreads, margarines, caviar (mainly lump fish caviar) spread, and other fish pastes, meat spreads, and the like.
• Other convenient supporting matrices are those comprising sugars or other carbohydrates, such as liquid or solid honey, molasses, syrup (e.g. corn syrup, glucose syrup), treacle, glycerol or "Maxim Energy gel"TM.
• viscosity of the solution and/or the composition as a whole may be increased by the addition of viscosifiers, gelling agents and the like.
• viscosifiers such components are well- known in the food industry and include, for example, plant-derived polysaccharides, gums and the like such as galactomannans, dextrans, guar gum, locust bean gum, xanthan gum and so on.
• Such viscosifiers, gels and the like may take the form of a supporting matrix, if desired.
• One preferred edible matrix comprises a gel prepared from concentrated Aloe Vera extract: a smooth creamy paste (suitable for packaging in a squeezable tube) may be prepared by mixing 5gms of creatine with (for example) 60ml of a concentrated Aloe Vera gel (such as that obtainable from Aloe Commodities Int. Inc., farmers Branch, TX75234).
• the supporting matrix may comprise a semi-liquid foodstuff such as a yogurt or other semi-liquid foodstuff.
• the present inventors have previously found that the conversion of creatine to creatinine in aqueous solutions can be markedly inhibited by creatinine itself, such that a mixture of creatine and creatinine can quickly reach equilibrium and the creatine becomes substantially stable. Without wishing to be bound by any particular theory, the inventors believe that the explanation for this observation is that the conversion of creatine to creatinine is a reversible reaction.
• the inventors have now found that, by providing creatine in solution together with an appropriate amount of creatinine the conversion of creatine to creatinine (even in an acidic composition) can be greatly inhibited or even substantially prevented even at ambient (i.e.2-39°C) temperature or above for long periods (30 to 95 days or more).
• the composition as a whole may conveniently be selected to be acidic (i.e. have a pH below 7.0) or even alkaline (eg 7.0 to 8.5) without significantly adversely affecting the stability of the creatine content of the composition.
• the composition desirably has a pH between 2,5 and 8.5, preferably between 3.0 and 7.0 and most preferably between 4.5 and 6.5.
• the composition has a pH in the range 4.5 to 5.5 which, to the human palate, has a refreshingly sharp taste without being too acidic.
• compositions in accordance with the invention are substantially stable so that creatine may be presented even in acidic formulations, contrary to the teaching of the art, in physiologically useful amounts, following storage for prolonged periods at ambient temperature.
• a physiologically effective amount of creatine is an amount sufficient to cause a measurable increase in the creatine content of the tissues of a subject following repeated consumption of the composition, relative to an initial baseline level.
• Methods of measuring the creatine content of the tissues of a subject are known (e.g. Harris, Hultman & Nordesjo (1974) Glycogen, glycolytic intermediates and high energy phosphates in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand. J. Clin. Lab. Invest.
• substantially stable is herein defined referring to a creatine/creatinine composition in which at least 75% (preferably at least 80%, and more preferably at least 85%) of the creatine in the composition immediately after formulation of the final product is unchanged, and therefore not converted into creatinine, for a period of at least (and preferably more than) 7 days' storage.
• the stability of creatine depends on the pH; the latter decreases with increasing temperature.
• the “final product” is the composition produced after all processing and production steps have been completed.)
• the inventors have found that a 20° C increase in temperature can decrease the pH by as much as 0.3 units.
• the temperature range to which the composition will be subjected is typically between 2 to 50°C.
• the composition will be sufficiently stable such that 75% of the creatine remains over the temperature range of 2 to 50° C following a period of at least 30 days, more preferably 60 days, and most preferably at least 120 days, during storage.
• the pH which must be measured at the temperature at which the solution will be stored
• the pH is altered by warming or cooling of a buffered solution and over the range of temperatures that a solution may be stored the equilibrium ratio of creatine: creatinine can vary greatly. However, if the composition is stable at 50° C then its creatine content will not decrease on storage at a lower temperature.
• the mole:mole ratio of creatinine to creatine to achieve stability of creatine is found to depend on the pH of the solution and ranges from 1:2 for pH 7 to 3.8:1 for pH 4.25. It is prefe ⁇ ed that the mole:mole ratio of creatinine to creatine is not more than 10:1. More prefe ⁇ ed is a ratio of not more than 5:1. Most prefe ⁇ ed is a ratio of creatinine to creatine which is not too high (since creatinine is an inactive ingredient) and the most prefe ⁇ ed pH is 5 to 7 where the mole:mole ratio of creatinine to creatine ranges from about 1.2:1 to 1:2.
• the creatinine can be added to the creatine as a pure substance or the creatinine can be manufactured in situ by heating creatine in solution, preferably at low pH e.g. pH 2 to 3. It is most convenient for the solution to be heated and held for at least 30 minutes at 90°C or more because these are the conditions often used for the sterilisation of a liquid for commercial sale. (Alternatively, an equivalent sterilising "heat dose" can be provided by heating to greater temperatures for shorter periods of time or vice versa.) In other embodiments, creatinine can be prepared by heating a solution of creatine for several hours at pH 2 to 3 and then adding it to a solution of creatine at higher pH (e.g.
• a further advantage of the invention is that it enables the provision of a composition which comprises the maximum concentration of dissolved creatine available (under the relevant conditions of pH and temperature), but using the least amount of creatine necessary, in a stable formulation, and so does not require the use of excess creatine.
• a prefe ⁇ ed embodiment of the invention is an aqueous drink, especially one at acid pH (i.e. below ⁇ H7), and in particular which has a pH in the range 4-6.5, especially 4.5-5.5, and which comprises at least 0.15g creatine (or creatine monohydrate and the like) per 100ml.
• the drink comprises at least 0.3g creatine (or creatine monohydrate and the like) per 100ml, more preferably at least 0.4g per 100ml, and most preferably at least 0.5g per 100ml.
• the composition may comprise a solution of creatine and creatinine in water without additional components (such as for example flavoring) as a solution in water e.g. mineral water or carbonated water using processes which are well known to those skilled in the art.
• the composition may comprise one or more further components to improve its palatability, stability, flavor or nutritive quality.
• these further components may include electrolytes, or may be selected from the group consisting of: vitamins, lipids, proteins, carbohydrates, polyols (such as ethylene glycol, glycerol, sorbitol etc.), amino acids, trace elements, colorings, flavors, artificial sweeteners, natural health and performance improving substances, anti-oxidants, stabilizers, preservatives, and buffers.
• Vitamins may be included with advantage in the composition of the invention. These may be added in amounts which range from 20 to 100% of their recommended daily allowance (RDA). The following are typical of those which are useful: vitamin E, vitamin C, thiamin, ribo flavin, niacin, vitamin B6, folacin, vitamin B12, biotin, and pantothenic acid.
• RDA recommended daily allowance
• lipid component may be desirable.
• the protein content (if any) may be present as soya or milk proteins (e.g. whey or casein).
• the carbohydrate content (if any) or the composition may be present as starch (particularly soluble starch) and/or sugars.
• the sugars which may be present in the composition include glucose, fructose, sucrose, lactose and maltose.
• Artificial sweeteners which can be used include Aspartame, Acesulfam K, Saccharin and Cyclamate. Almost any desired flavoring can be added, most preferably fruity flavors such as be ⁇ y, lemon, orange, papaya and grapefruit. However, at less acidic pHs (e.g. over 5.0) other flavors such as chocolate, malt, caramel and other flavors suitable for "milky" drinks can be used. Citric acid may also be used as an acidulant and citrate and phosphate (e.g. sodium citrate or phosphate) as a buffering agent. Other buffering agents may be used to regulate the acidity of the drink. Also other natural health improving substances may be added in physiologically active amounts.
• citrate and phosphate e.g. sodium citrate or phosphate
• Pau D'Arco tea Ginseng, Suma tea, Ginkgo, bee pollen, my ⁇ h, hydroxy-methy-butyrate, glutamine, di- tri-, and polypeptides containing glutamine, ribose, caffeine, and lipoic acid.
• Preservatives can be provided typically by potassium benzoate and/or potassium sorbate.
• Coloring can be provided, typically by using a cold water soluble colorant such as beta- carotene. Other suitable colorings will be apparent to those skilled in the art.
• a clouding agent may be included in the composition, if desired, to improve the appearance of the composition.
• the mineral and trace elements can also be added in any type or form which is suitable for human consumption. It is convenient to provide the calcium and potassium in the form of their gluconates, phosphates or hydrogen phosphates, and magnesium as the oxide or carbonate, chromium as chromium picolinate, selenium as sodium selenite or selenate, and zinc as zinc gluconate. Typically the amounts are:- sodium at 400mg/liter, calcium at lOOmg/liter, chloride at 600mg/liter, potassium at 200mg/liter, magnesium at 75mg/liter and phosphorus at 50mg/liter, chromium at 125 ⁇ g/liter, selenium at 125 ⁇ g/liter and zinc at 15mg/liter.
• the amount of creatine (calculated as the monohydrate from hereon) per litre or per Kg of prepared composition may range from 1.5g to 24g with a preferred content of about 12g per liter.
• the normal serving size is in the range 200-750ml, providing about 2 to 7g, preferably about 5g of creatine.
• the recommended consumption is about 2.0 liters per day, divided in 4 or 5 parts per day to achieve creatine saturation. This is followed by 1 serving of 250-750mI per day containing about 2-3g of creatine to provide a sufficient level of creatine to maintain saturation.
• the amount of creatine per lOOg may range from 1 to 80g (calculated as creatine monohydrate from hereon)
• the prefe ⁇ ed portion size is in the range 5 to lOOg providing between 2 to lOg (preferably 5g) of creatine.
• the recommended consumption is a suspension containing 10 to 25g per day divided into 4 or 5 parts per day to achieve maximum creatine elevation in the tissues.
• lower doses over a longer period e.g. 3g daily for 4 weeks
• one serving of suspension daily containing 3 to 5g creatine to provide a maintenance level of creatine.
• the invention also relates to a method of making the composition defined above.
• the invention provides a method of making a composition for human consumption, the method comprising the step of providing, in the same composition, creatine and sufficient creatinine to render the creatinine substantially stable (as herein defined) when the composition is mixed with an aqueous medium.
• the aqueous medium is water or an aqueous solution.
• the method will also normally include the step of providing water or an aqueous solution, preferably in sufficient amount so as to dissolve substantially all of the creatine and creatinine in the composition.
• solid creatine and solid creatinine may be added (simultaneously or separately) to water or an aqueous medium; or water or an aqueous medium may be added to solid creatine and/or creatinine.
• the second aspect of the invention provides a method of preparing a creatine containing composition for human consumption in which the creatine is substantially stable (as herein defined), the method comprising the steps of: providing a solution of creatine; and subjecting the solution of creatine to suitable conditions so as partially to convert the creatine to creatinine, thereby forming sufficient creatinine to render the creatine in the resulting composition substantially stable (as herein defined).
• the method typically will comprise the further step of packaging the composition in suitable containers e.g. glass or plastic bottles, foil sachets, aluminium cans etc.
• the method is such that subjecting the solution of creatine to suitable conditions involves heating the solution above average ambient temperature.
• the solution is heated to 90°C for 30 minutes.
• the invention provides a method of preparing a creatine containing composition for human consumption in which the creatine is substantially stable (as herein defined), the method comprising the steps of: providing a solution of creatine; providing a solution of creatinine; and mixing the solutions so as to form a resulting composition in wich there is sufficient creatinine to render the creatine substantially stable (as herein defined).
• the pH of the solution of creatinine is preferably lower than the pH of the solution of creatine.
• the pH of the solution of creatinine is in the range 2 to 3
• the pH of the solution of creatine is preferably in the range 4.5 to 7 with adjustment, if necessary, of the final pH to the desired level.
• the invention provides a method of preparing a creatine containing composition for human consumption in which the creatine is substantially stable (as herein defined), the method comprising the steps of: providing solid creatine; providing solid creatinine; and mixing the two solids so as to provide a resulting composition which, when dissolved in aqueous solution, provides a composition in which there is sufficient creatinine to render the creatine substantially stable (as herein defined).
• this method will further comprise the step of adding sufficient water or aqueous solvent to substantially dissolve the resulting composition.
• the water or aqueous solvent may be pre-sterilised by heat treatment and/or filtration.
• the invention provides a method of preparing a creatine containing composition for human consumption in which the creatine is substantially stable (as herein defined), the method comprising the steps of: providing solid creatine and solid creatinine, or an aqueous solution of creatinine, the creatinine being in sufficient quantity to render the creatine substantially stable (as herein defined); mixing the solid creatine with the solid creatinine or aqueous solution of creatinine; and adding to the mixture an edible supporting matrix.
• Figures 1 and 2 are graphs of the creatine concentration (as g per 100ml, and as a percent of the initial concentration, respectively) in solutions of different pH against time (as described in Example 2);
• Figure 3 is a graph of the mole:mole ratio of creatinine (Cn) to creatine (Cr) in solutions of different pH's after 124 days incubation (as described in Example 2);
• Figures 4 and 5 are graphs of a creatine concentration (as g per 100ml, and as a percent of the initial concentration, respectively) against time, where a mixture of creatine and creatinine in solutions of different pH's were incubated for up to 95 days (as described in Example 3);
• Figure 6 is a graph of the mole:mole ratio of creatinine to creatine against pH for solutions stable after 6 weeks incubation at 39°C (as described in Example 5);
• Figure 7 is a graph of the mole:mole ratio of creatinine to creatine against pH for solutions stable after 6 weeks incubation at 2°C, 22°C and 39°C (as described in Example 5);
• This example relates to a convenient in vitro assay method for determining the concentration of creatine in a solution.
• the object of this trial was to determine the stability of creatine when heated at 90°C at different pH's and the solutions left at room temperature for up to 124 days.
• the conversion of creatine to creatinine generally occurs very rapidly.
• Solutions in water of 2g creatine monohydrate in 100ml 0.1M citric acid - 0.1M potassium phosphate buffers at pH's 3, 4, 5, 6 and 7 were heated at 90°C for 30 minutes. The solutions were quickly cooled, the pH (which had changed) re-measured and then left at room temperature as described in Example 1. Aliquots were taken after 7, 15, 29, 43, 57, 89 and 124 days and stored at -30°C and subsequently analysed for creatine. The pH of each sample was measured. The concentration of creatinine was estimated from the difference between the starting level (2g creatine monohydrate) and the measured level of creatine (calculated as the monohydrate).
• the object of this trial was to determine the effect of creatinine in the proportion of l :l(w/w) to creatine monohydrate on the stability of creatine at different pHs after heating the mixture for 30 minutes at 90°C. Quantities of 1.5g creatine monohydrate and 1.5g creatinine were dissolved in 100ml of 0.2M citrate - 0.2M potassium phosphate buffers at pHs 3, 4, 5, 6 and 7. The solutions were heated at 90°C for 30 minutes, cooled, the pH re-measured and left at ambient temperature (22 °C ) for up to 95 days.
• Creatine stability occu ⁇ ed at all pH's. At pH's 5, 6 and 7 there was even a trend for the creatine concentration to increase
• creatine In the presence of a sufficient quantity of creatine (which for pHs 5, 6 and 7 was equal to or less than a weight ratio creatinine: creatine monohydrate of 1:1), creatine is exceptionally stable, even when heated for 30 minutes at 90°C. With an insufficient quantity of creatinine (for samples at pHs 3 and 4) heating for 30 minutes at 90°C resulted in production of sufficient creatinine also to render the remaining creatine stable for at least 95 days thereafter.
• This example illustrates a method of heating a solution of creatine to form creatinine and then adding it to a flavored drink containing creatine to give a concentration which is substantially stable. Simultaneously it is desired that the concentration of creatine remaining is close to its maximum solubility such that it will not precipitate out in the refrigerator at 3°C. This is a requirement for most beverages since they may be chilled in a refrigerator before consumption.
• Step 1 5g of creatine monohydrate were dissolved in 100 ml 0.1 M citric acid (pH 3) and heated at 90°C for two hours. This converted most of the creatine into creatinine. The solution was cooled to room temperature.
• Step 2 A solution was prepared containing 5g creatine monohydrate in 650 ml 0.1M citrate buffer at pH 5 at room temperature, without heating. In addition, the solution contained 15 per cent Aloe Vera juice, flavoring and dextrose to sweeten.
• Step 3 Solutions from steps 1 and 2 were then mixed together and heated at 90°C for 30 minutes to sterilise the mixture and then placed in a glass or plastic bottle and stored at 22°C.
• the 5g creatine monohydrate added in step 2 remained substantially stable upon formulation of the final product.
• solutions 2b and 2d were mixed in various proportions to obtain solutions of 67.06mM creatinine at the same pH values identified in 3 above.
• the ratios predicted by this line are identical to those shown in Fig 3 obtained after 17.7 weeks incubation at 22°C, but where the solutions were initially composed only of creatine and no creatinine. This confirms the data in the present example. Discussion and Conclusions
• the ratio of creatinine to creatine was 2.1:1. This is the upper limit considered as being practical for a stable drink containing creatine. Below a final pH of 4.6, the amount of creatinine to maintain the stability of creatine is excessive wasteful of material and impractical. At a final pH of 5.2 the ratio is about 1.0:1 which is a practical level and provides a palatable drink with an acidic pH. Compositions with pHs where the ratio is less than 1.0:1 are also practical and have the advantage of economy of materials, but have the disadvantage of not being so acidic and less palatable.
• compositions recommended as useful for drinks are similar as those described above for room temperature.
• 39°C considering to be the extreme of a high ambient temperature
• the lowest pH supporting a mole:mole ratio of creatinine to creatine of 1.0:1 is 5.2-5.5 and defines the lowest pH for the practical range of compositions for drinks.
• the most important factor influencing the ratio of creatine to creatinine at equilibrium is pH. If creatine and creatinine are mixed in the proportions at which they occur at equilibrium at a specified pH then these compositions will be immediately stable, as will also be the pH. When the initial composition is either side of that at equilibrium then concentrations of each will move towards those at equilibrium. If this involves formation of creatinine then the pH of the composition will increase, whereas if this involves formation of creatine then pH will decrease. The extent to which pH is changed will depend upon the absolute change in creatine or creatinine which must occur to reach equilibrium and the buffering capacity of the media. The time taken to reach equilibrium will be determined by how far the initial molermole ratio differs from that at equilibrium.
• compositions are prepared in which the concentrations of creatine and creatinine are significantly removed from those at equilibrium, and, where these solutions are then warmed or cooled for prolonged periods, then both factors described above will apply. In all of these cases, however, the extent of change may be minimised if the immediate influence on pH of warming or cooling of the base solution (i.e. the solution in the absence of added creatine and creatinine) is known and by applying the mole:mole creatinine to creatine ratios described in figs 6 to 8 when preparing the composition.
• Table 3 shows the creatinine to creatine mole:mole ratios of solutions of different pH at equilibrium and the co ⁇ esponding concentrations of creatine (calculated as the monohydrate) and creatinine in a 500ml drink.
• concentration of creatine itself has been fixed in all cases to 5g creatine monohydrate, and the concentration of creatinine allowed to vary accordingly.
• Table 3 Estimated creatine and creatinine contents of a 500ml drink of different pH's stored at 22°C for 6 or more weeks.
• This example describes the detailed formulation of an acidic composition in accordance with the invention.
• the composition takes the form of a dry powder, which is to be added to water to constitute a foodstuff comprising creatine, creatinine and Aloe Vera in which the creatine is substantially stable.
• the above mixture when suspended in one liter of matrix or dissolved in one liter of water provides, per 330ml serving, about 4.4g creatine, 8.5g carbohydrate, 1.25 g Aloe Vera extract, (equivalent to 250 ml juice), energy 34kcal (assuming a zero calorie content for the supporting matrix), calcium, potassium, magnesium and vitamins (vitamin E 3.4 mg, vitamin C 16.2 mg, thiamin 0.3mg, riboflavin 0.4mg, niacin 5 mg, vitamin B6 0.4 mg, folacin 85 ⁇ g, vitamin B12 0.9 ⁇ g, Biotin 0.08mg and pantothenic acid 2.2mg) and traces of protein, fat, and fiber.
• the solution has a pH of about 5.0.
• the creatine is substantially stable for at least 7 days at room temperature.
• This example illustrates the method of providing a suspension of creatine and a sufficient quantity of creatinine in an edible supporting matrix to render the creatine substantially stable at ambient temperature.
• Creatine monohydrate (1.7g) is dissolved in 100ml of 0.1 M citric acid (to give a pH of 2.5-3) and the solution heated for five hours at 90°C. This converts 75 to 100 per cent of the creatine into creatinine and the pH is then raised to 5.0 by the addition of 100ml of 0.1 M potassium phosphate solution.
• Four grams of xanthan gum is then added and heating continued until the gum dissolved. The mixture is then cooled to 40°C.
• a slu ⁇ y of 22g micronised creatine in 20ml water is added, and the mixture well sti ⁇ ed for three minutes using a vortex mixer to give a gel in which the micronised creatine is uniformly suspended.
• the whole mixture is subsequently cooled rapidly to room temperature at which point the suspension forms a solid or semi-solid gel with a creatine content of lOg per 100ml which substantially stable at 22°C for at least 30 days.

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