MXPA98009764A - Improvements in, or related to, compositions containing creat - Google Patents

Abstract

The present invention relates to an acid composition for human consumption, comprising creatine. In particular, the composition is conveniently an isotonic beverage for storage at 4 ° C, or it is a stable powder that can be stored at room temperature.

Description

IMPROVEMENTS IN PTCT.af EQNADAS WITH COMPOSITIONS CONTAINING CREATIN FIELD OF THE INVENTION This invention relates to compositions for human consumption comprising creatine, and to a method for providing stable compositions containing creatine.

ANTECEDENTS OF THE TJNVENTION Governments are currently concerned with the high incidence of obesity (and less degrees of weight gain) in populations, since it represents a known risk factor for coronary heart disease, hypertension and diabetes. In addition to diet modification, the main thought of treatment and weight maintenance after weight loss is physical exercise. Now it is suggested by experts that the diet itself is insufficient in the long term to maintain weight loss without altering the lifestyle, in particular to perform more exercise. However, one of the problems experienced by overweight people is that they find physical activity tired and fatigued easily. There is a need for a regimen which makes obese people fatigue less so that they can exercise for longer periods, burn more calories and lose more weight, or maintain their weight better after losing weight. In addition, in recent years there has been considerable interest among athletes in creatine, which occurs abundantly in skeletal muscle. Creatine plays a basic role in the regulation and homeostasis of skeletal muscle energy metabolism and it is now generally accepted that the maintenance of phosphocreatine availability is important for the continuation of muscle force production. Although creatine synthesis occurs in the liver, kidney and pancreas, it has been known for some time that oral ingestion of creatine can help the total body pool of creatine, and it has been shown that ingestion of 20 to 30 g of creatine per day for several days can lead to a greater than 20% increase in the total creatine content in human skeletal muscle. Therefore, document O94 / 02127 describes the administration of creatine in amounts of at least 15 g (or 0.2-0.4 g / kg body weight) per day, for at least 2 days, to increase muscular endurance. In fact, it was later found that, after several days of supplementation (20 g per day) with creatine, no more than 2 or 3 g per day are required to maintain the saturation of the body stores. Supplementation with creatine in an appropriate dose can provide improvement to athletes involved in high-wear events which include all events that last from a few seconds to a few minutes (such as start of race, swimming, weight lifting, etc.). Resistance in events that last more than about 30 minutes seems not to be affected with the creatine supplement. Creatine is a normal food component and is not a drug and its use is not contrary to official regulations. The greatest benefits of supplementation can be experienced by vegetarians or those who do not eat meat or fish, since these people tend to have a low content of muscle creatine. During the last years there has been considerable interest in the use of isotonic drinks that yield to physical exercise. Human body fluids comprise water and substances dissolved therein, such as mineral salts known as electrolytes. These allow electrical impulses to stimulate muscular action. Isotonic drinks replace essential electrolytes lost in sweat during and / or after exercise. The term isotonic is applied to beverages that contain the same concentration of minerals as body fluids and in which the osmotic pressure is the same as that exerted by human body media. The most important electrolytes used in isotonic drinks are sodium, chloride, potassium, calcium, magnesium and phosphorus. The isotonic drinks can be made already diluted with water or they can be conveniently packed in sacks or cans as a powder which must be subsequently mixed with non-foamy or carbonated water to provide a refreshing-tasting drink, for example of citrus flavor. It is well known that creatine is unstable in aqueous solutions at acidic or neutral pH, and becomes a related compound, creatinine. It is highly significant that creatinine does not have an improving effect on muscle function and is excreted from the human body as a waste product in urine. In view of the foregoing, EP 0 669 083 discloses that aqueous beverages for human consumption that comprise creatine should be weakly alkaline, in order to avoid the conversion of creatine into creatinine, and this has become the generally accepted opinion.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, the invention provides an acid composition for human consumption, comprising creatine. The term "acid" is intended to mean that the composition has a pH less than 7.0. In particular, the composition desirably has a pH between 2.5 and 6.5, preferably between 3.0 and 6.0. Typically, the composition has a pH in the range of 3.5 to 5.5 which, for the human palate, has a strong refreshing flavor without being too acidic.

The creatine content of the composition may be present as any active form of creatine (eg, creatine phosphate) but creatine monohydrate is found to be particularly convenient as a source of creatine. The composition may be in the form of a dry powder or may be provided in liquid or semi-liquid form (for example as a beverage or yogurt, respectively). In preferred embodiments, the composition is a beverage which is isotonic (ie, corresponds to the osmotic potential of human body fluids) and / or comprises electrolytes. Conveniently, the composition will be constituted of electrolytes and will be isotonic. The present inventors have found that the conversion of creatine to creatinine to acidic pH is actually low enough to allow physiologically useful amounts of creatine to remain in the composition after considerable periods of time, so that creatine may be present in formulations acids, contrary to the teaching of the technique. In particular, the conversion of creatine to creatinine can be greatly inhibited by storage (for example in commercial refrigerant cabinets at 4-8 ° C) of the composition at lower temperatures than in the environment. Therefore, in a second aspect, the invention provides a method for storing a liquid or semi-liquid, acidic composition comprising creatine for human consumption, the method comprising storing the composition below room temperature, typically in a commercial refrigerating cabinet. at 4-8 ° C of the conventional family class for any medium or large sized retailer. Typically, the composition is an aqueous (preferably isotonic) drink or a yogurt or similar semi-liquid food. The beverage may be non-frothy or carbonated, and preferably comprises a citrus flavor. Alternatively, the composition can be provided as a dry powder which, when mixed with (preferably dissolves in) a predetermined volume of liquid (for example of substantially neutral pH) gives rise to an acid solution. The creatine content of the composition is stable as a dry powder at room temperature. The appropriate doses of the powder can then be dissolved as required, to form fresh beverages with substantially no decrease in creatine content. The powder can be dissolved in any suitable liquid (for example water, milk) or a semiliquid (for example yogurt). Accordingly, in a further aspect, the invention provides a method for delivering a composition containing creatine for human consumption, the method comprising providing an acidic composition containing creatine as a stable, dry powder, which, when mixed with water or a suitable aqueous solution produces an acid beverage comprising physiologically effective amounts of creatine. Typically, the powder is such that, when a certain amount is dissolved in a predetermined volume of water, it provides an isotonic beverage. Desirably, the powder is provided as unit doses (of about 10-20 grams) which can be dissolved in 200-350 ml of water to provide an isotonic beverage. The unit doses are conveniently supplied individually packaged in pouches, bags, packages, cylinders, bottles or other suitable packaging means. Preferably, the package is hermetically sealed (for example, a thin sheet pouch) to prevent the ingress of water or steam. Sometimes it may be desirable to provide a volumetric measuring means with the package to allow the user to measure an appropriate volume of water in which to dissolve the contents of the package. Typically, this may take the form of a water-tight container (eg, of plastic material) with one or more graduations to indicate a certain volume. The container may take the form of a pitcher with a spout or similar container, to retain water in which the composition is to be dissolved, and from which the resulting solution may be ingested. Preferably, the composition will consist of one or more additional components to improve its palatability, stability, flavor or nutritional quality. These additional components may include electrolytes, as already mentioned above, or may be selected from the group consisting of: vitamins, lipids, carbohydrates, amino acids, trace elements, colorants, flavors, artificial sweeteners, antioxidants, stabilizers, preservatives and buffers . People on diets to lose weight often receive a reduced intake of vitamins, so that these should be included with advantage in the composition of the invention. The following vitamins can be added in amounts ranging from 20 to 100% of the recommended daily requirements (RDA). The following are typical of those which are useful: vitamin E, vitamin C, thiamine, riboflavin, niacin, vitamin B6, folacin, vitamin B12, biotin and pantothenic acid. In some cases, a lipid component may be desirable. The carbohydrate component (if any) of the composition can be present as starch (particularly soluble starch) and / or sugars. The carbohydrates used in the invention can preferably be used in amounts which are consistent with the isotonicity of the composition in its preferred embodiments, taking into consideration the effect of the creatine content. The osmolarity of the beverage should preferably not exceed 320 mOsm + or - 10%. The sugars which may be present in the composition include glucose, fructose, sucrose and maltose.

Artificial sweeteners which may be used include aspartame, acesulfan K, saccharin and cyclamate. Almost any desired flavoring can be added, more preferably citrus flavors such as lemon, orange and grapefruit. Citric acid can also be used as an acidulant and as a buffering agent. Colorants can be provided, typically by the use of a cold water soluble dye such as beta carotene. Other suitable coloring substances will be apparent to those familiar with the art. A clouding agent may be included in the composition to improve the appearance of the finished beverage and differentiate it from a lemonade. You can add minerals of any type or shape which provide in combination, the correct osmolarity and / or containing electrolytes in quantities which approximate the composition with body fluids. It is convenient to provide calcium and potassium in the form of its phosphates or acid phosphates, and magnesium as the oxide or carbonate. Typically, the amounts are: sodium at 400 mg / liter, calcium at 100 mg / liter, chloride at 600 mg / liter, potassium at 200 mg / liter, magnesium at 75 mg / liter and phosphorus at 50 mg / liter. The amount of creatine per liter of beverage prepared can vary from 0.5 to 30 g, with a preferred content of approximately 12 g per liter. The normal portion size is in the range of 250-330 ml, which provides approximately 3 g of creatine. During the first 4 days of creatine supplementation, the recommended intake is 1.5 liters per day divided into 4 to 5 parts per day to obtain creatine saturation. This is followed by a drink of 250 ml per day containing 3 g of creatine to provide a maintenance concentration of creatine. In some embodiments, the composition may additionally be comprised of pyruvate and / or dihydroxyacetone. Pyruvate and dihydroxyacetone are ergogenic compounds present in the body and have been shown to improve submaximal resistance (RT Stanko et al., 1993 Sports Sciences 11, 17-23) and when substituted by carbohydrates in the diet they are useful for increasing weight loss in low energy diets (RT Stanko et al., 1992, Am. J. Clin. Nutr 56, 630-5). Pyruvate can be provided as a salt, preferably the sodium, potassium, magnesium or calcium salt. Pyruvate can be used without dihydroxyacetone or as a mixture with it, for example, as a 1: 3 mixture (P: DHA). The total amount of pyruvate and / or DHA per 250 ml portion of the composition may be in the range of 1 to 25 g, conveniently 5-15 g. The invention will now be further described by way of illustrative example and with reference to the accompanying drawings in which: Figures 1 and 2 are graphs of creatine concentration against time; and Figures 3-6 are graphs of creatine% versus time.

EXAMPLES Example 1 These examples describe the detailed formulation of an acid composition according to the invention. The composition takes the form of a dry powder, which must be dissolved in water to constitute the isotonic drink comprising creatine.

Ingredients Dextrose monohydrate 300 g Citric acid 32 g Pectin (stabilizer) 6.0 g Salt 5.0 Trisodium citrate 5.0 Beta carotene 3.0 Potassium chloride 2.9 Melon grape flavor 2.9 Tricalcium phosphate 2.1 g Heavy magnesium carbonate 2.1 g Vitamin premix 1.8 g Lemon flavor 1.4 g Orange flavor 1.4 g Aspartame 1.0 g Creatine monohydrate 88 g When 63 g of the above mixture are dissolved in 1 liter of water, approximately 3 g of creatine, 203 kg of energy (48 kcal), 11.1 g of carbohydrates, 156 mg of chloride, 100 mg are provided per 250 ml portion. sodium, 52 mg of potassium, 26 mg of calcium, 19.5 mg of magnesium, 13 mg of phosphorus, vitamins (3.4 mg of vitamin E, 16.2 mg of vitamin C, 0.3 mg of thiamin, 0.4 mg of riboflavin, 5.0 mg of niacin, 0.4 mg of vitamin B6, 85 μg of folacin, 0.9 μg of vitamin B12, 0.08 mg of biotin and 2.2 mg of pathogenic acid) and traces of protein, fats and fiber. This provides a refreshing isotonic beverage containing electrolytes and creatine which is relatively lower in calories compared to conventional isotonic drinks and has a pH of about 3.8.

This example relates to another embodiment of the invention. The formulation is as in Example 1 above, except that 300 g of dextrose monohydrate is suppressed and the content of aspartame is increased to 2.5 g to compensate. When 5.3 g of this formulation dissolves in 250 ml of water, an almost calorie-free beverage containing creatine and electrolytes is provided which, while not isotonic, is nutritionally useful for those who wish to lose or maintain their weight.

Example 3 This example relates to another embodiment of the invention. The formulation is as in Example 1 above, except that half of dextrose monohydrate is abolished and replaced by the same weight of sodium, calcium or potassium pyruvate, together with the addition of 0.75 g of aspartame (which provides an amount total of 1.75 grams of aspartame). A typical portion of this formulation is 15.75 g mixed in 250 ml of water.

Example 4 This example relates to a study of the stability of creatine under sterile conditions at pH over a period of two weeks. A dry powder composition according to the invention is prepared and stored in 14 gram samples. The composition is essentially as described in example 1. Each sample of 14 g of the composition consists of approximately 3 g of creatine. 14 g of the powder composition are dissolved in 400 ml of distilled water, and the solution is incubated under sterile conditions at 25-26 ° C for 2 weeks. The pH of the composition at the beginning of the experiment is 3.66. 5 ml aliquots are removed aseptically from the solution during the course of the experiment and analyzed to determine the creatine and creatinine concentration. These determinations were carried out simultaneously by reversed phase ionic phase high resolution liquid chromatography, according to the method of Murakita (1988 J. or Chromatography 432, 471-473). The experiment is carried out in triplicate and the results are shown below in table 1.

Table 1 These results are also represented graphically in figures 1-3. Figure 1 is a graph of an average concentration of creatine (black circles) or the concentration of creatinine (white circles) in mmoles / liter, against time (measured in hours, days or weeks). Figure 2 is a similar graph showing the creatine or creatinine mean of the composition, in grams / 400 ml, against time. Figure 3 is a graph showing the percentage of unconverted creatine (black circles) or the percentage of creatine converted to creatinine (white circles) against time. From these data, it is evident that acidic creatine solutions can be stored at room temperature for 24 hours with very little loss of creatine. Longer storage (for 2-3 days) is possible without a serious loss of creatine).

Example 5 This example is related to a study of creatine stability for 3 days in aqueous solutions at different pH values. 42 grams (three samples of 14 g) of the powder formulation described in the preceding example are dissolved, in 750 ml of distilled water heated to 25 ° C, seven aliquots of 100 ml (called AG, respectively) are extracted into beakers. precipitates of polystyrene of known weight and are reweighed. The pH of the aliquots is adjusted to the desired values (A = pH 2.5, B = 3.5, C = 4.5, D = 5.5, E = 6.5, F = 7.5, G = 8.5) using 50% acetic acid or 5N KOH . After adjusting the pH, the beakers are reweighed to ensure that the increase in volume is less than 5% (i.e., less than 5 ml). The samples are kept at 25 ° C for 24 hours and 5 ml aliquots are extracted for creatine and creatinine concentration analysis, (as previously described) at the time points of 0.5 h, 4 h, 8 h, 1 day and 3 days. The pH of the solutions was also tested, to ensure that the pH is not greatly altered during the development of the experiment. These results are shown in table 2 below.

Table 2 With reference to figure 4, the figure shows a graph of% creatine that remains against time (measured in hours or days) for the A-F solutions. The results for solutions A (pH 2.5) and G (pH 8.5) are omitted for clarity. The legend is as follows: black squares = solution B (pH 3.5), white squares - solution C (pH 4.5), white triangles = solution D (pH 5.5), black triangles = solution E (pH 6.5) and white circles = solution F (pH 7.5). It can be seen that, in general, the lower the pH the faster is the conversion of creatine to creatinine, but even in solutions of pH 4.5 or similar, they are reasonably stable for up to 3 days. The decomposition after 3 days at pH 5.5, 4.5 and 3.5 is 4%, 12% and 21%, respectively. In fact, it has been found that an exception to this general rule is that creatine is more stable at pH 2.5 than at pH 3.5. After 3 days, the decomposition at pH 2.5 is found to be "13%, similar to that which occurs at pH 4.5.

Example $ This example is related to a study of creatine stability over a period of 52 days in aqueous solutions at different pH values that are maintained at a lower temperature than the environment (specifically, 4 ° C). First, because creatine has poor solubility in water at 4 ° C, an experiment is performed to ensure that the creatine concentrations used in the determination of stability do not lead to creatine precipitation for a period of 5 weeks. The determination of solubility was carried out as follows: 1.2 g of creatine monohydrate are dissolved in 100 ml of buffer solutions (prepared by mixing 200 mM K2HP04 and 200 mM acetic acid, and adjusting the pH by the addition of 5M KOH) apH 3.5 , pH 5.0, pH 6.0 and pH 7.0 at room temperature.

The dilutions were made with distilled water for each pH value: A) without dilution B) - 9: 1 (buffer: water) C) - 8: 2"D) - 7: 3" E) - 6: 4 F) - 5: 5" The final solutions were stored in capped plastic tubes. The tubes are stored at 4 ° C, shaken every 2 hours or similar and the time of occurrence of precipitation is noted. The relative amount of precipitation is recorded after storage for 78 hours at 4 ° C and the results are presented below in Table 3. Tube D (7: 3 dilution) has the highest concentration of creatine which does not show precipitation after 78 hours. The concentration of creatine in tube D is 8.4 g / 1. Accordingly, the stability determination experiments were performed using the same initial concentration of creatine.

Table 3 Relative precipitation: *** = heavy; ** = moderate; * = light; = none The determination of stability was made as follows. 14 g of the formulations described in Example 4 are dissolved in 250 ml of distilled water. Additionally, 14 g of a second formulation is dissolved in 500 ml. The second formulation does not contain any creatine, but otherwise it is identical to the formulation described in example 4. 107 ml of a second solution is added to the first solution, resulting in a 7: 3 dilution. Four aliquots of 60 ml are removed and the pH adjusted with 5M KOH to: A - unadjusted pH; B - pH 5.0; C - pH 6.0; D - pH 7.0. Aliquots of 40 ml are extracted for storage in plastic tubes at 4 ° C. Samples of 0.5 ml of AD are extracted and diluted directly in 100 ml of distilled water at 0 h, 2 d, 7 d, 14 d, 28 d, 35 d and 52 d for creatine and creatinine analysis by CLAP, as describes previously. The pH of the samples is also determined to ensure that it has not changed during the course of the experiment. The results are shown below .

Table 4 pH of the samples over the course of the experiment The results of the creatine stability analysis are shown below in table 5.

Table 5 - Creatine stability during 52 days of storage at 4 ° C. ÍCrl or fCnl in mmol / l day 0% of Cr remaining on the day [Cr] [Cn] 0 2 7 14 28 35 52 A 60.79 0.00 100 99.4 98.6 97.0 94.0 92.7 92.1 B 55.40 0.00 100 100 99.4 98.8 97.0 96.0 95.8 C 60.32 0.00 100 100 99.7 99.7 99.3 98.6 98.6 D 59.68 0.00 100 100 100 100 99. 99.6 99.4 The above results are also presented graphically in Figure 5. Figure 5 is a graph of creatine% that remains against time (in days). White circles with solid lines show results for solution A, black circles with dotted lines show results for solution B, white circles with a dashed line show results for solution C, and black circles with a line with points and ions shows the result for solution D. These data show that, even at a pH as low as 3.5-3.6 after storage for 5 weeks at 4 ° C, only 7.3% of the creatine had converted to creatinine, and there was very little change after day 52, indicating that an equilibrium has been reached that leaves significant amounts of creatine available for physiological benefit. Therefore, an acid formulation comprising creatine can be prepared and stored successfully especially with storage at temperatures below ambient.

Example 7 This example is related to a study of the stability of creatine during several weeks in different commercially available yogurts (acids), during storage at 4 ° C. The study was conducted as follows. 0.5 g of monohydrated creatine was mixed with 100 g of a commercially available yogurt to provide a creatine concentration of approximately 3.4 mmol per 100 g. The supplemented yogurt is placed in a common refrigerator set at 4 ° C. At various times, 2 g of the supplemented yogurt are taken and placed in 100 ml of distilled water. Filter 1 ml of the resulting solution using a Whatman microfilter with 12 kilodalton pore size, and the clear filtrate is tested to determine creatine and creatinine concentrations as previously described. Three different types of yogurt (purchased from Tesco's stores) were used in the experiment: a low-fat natural yogurt, a "healthy eating bio" yogurt, "healthy eating bio" and a Fage Greek yogurt, the results of the creatine analysis were shown below in table 6, and are graphically depicted in figure 6. Figure 6 shows a plot of% creatine remanent against time (in days) The tables show the results for low fat yogurt, the circles show the results for the "healthy eating" yogurt and the triangles show the results for the Greek yogurt The creatine stability in the different yoghurts is remarkably similar The amount of conversion of creatine to creatinine is about 6% or less after 31 days of storage at 4 ° C.

Table 6 - Creatine stability in three different commercially available yogurts The presence of live bacteria in yogurt does not seem to have any harmful effect. Therefore, yogurt represents an extremely useful vehicle for a composition containing creatine, especially as yogurt that are conventionally handled and stored at temperatures below the ambient - the presence of creatine in the yogurt does not need any additional handling requirement in relation to at storage temperature.

Claims (15)

1. An acid composition for human consumption, characterized in that it comprises creatine and one or more additional components that are selected from the group consisting of: vitamins, lipids, carbohydrates, amino acids, trace elements, colorants, flavors, artificial sweeteners, antioxidants, stabilizers, preservatives and shock absorbers.

2. The composition according to claim 1, characterized in that the composition is a coil which is isotonic and / or comprises electrolytes.

3. The composition according to claim 1 or 2, characterized in that the composition is an isotonic beverage comprising electrolytes.

4. The composition according to any of claims 1-3, characterized in that it has a pH in the range of 2.5-6.5.

5. The composition according to any of the preceding claims, characterized in that it has a pH in the range of 3.0 to 6.0.

6. The composition according to any of the preceding claims, characterized in that it comprises pyruvate and / or dihydroxyacetone.

7. The composition according to any of the preceding claims, characterized in that it comprises pyruvate as the salt or salts of sodium, potassium, calcium or magnesium thereof.

8. The composition according to claim 1, characterized in that the composition is a dry, stable powder.

9. The composition according to claim 1, characterized in that when mixed with a predetermined volume of liquid, it produces a beverage according to any of claims 2 to 7.

10. The composition according to any of the preceding claims, characterized in that it is provided as a unit dose.

11. The composition according to claim 1, characterized in that the composition is a yogurt or other semiliquid food.

12. A method for delivering a composition containing creatine for human consumption, the method is characterized in that it comprises providing an acidic composition containing creatine as a stable, dry powder which, when mixed with water or a suitable aqueous solution, provides an acidic beverage. comprising physiologically effective amounts of creatine.

13. The method according to claim 12, characterized in that the powder is provided in unit doses which, when mixed with a predetermined volume of water, produce an isotonic beverage.

14. A method for storing a liquid or semi-liquid composition for human consumption, comprising creatine, the method is characterized in that it comprises storing the composition below room temperature.

15. The method according to claim 14, characterized in that the composition is stored at 4-8 ° C.