JP2006328079A - Composition stimulating specific metalloenzyme - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition produced preferably in the form of a drink capable of promoting the metabolism of alcohol and acetaldehyde to reduce the load on a human body and, accordingly, effective for preventing excessive alcohol intake, sick from drinking and hangover. <P>SOLUTION: The invention provides a stable composition, preferably a refreshing drink promoting the decomposition of alcohol and acetaldehyde in the body and containing a synergistic combination of caffeine, herb and fructose. Preferable embodiment of the composition contains caffeine, guarana caffeine, mate, eleutherococcus, Panax ginseng, ginger, glycyrrhiza glabra (licorice), fructose and additional components (sugar, flavor, colorant, vitamins, stabilizer, whole fruit powder, etc.) and, as necessary, gingko. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a composition that is preferably manufactured as a beverage that can promote the metabolism of alcohol and acetaldehyde to reduce the burden on the human body, and thus is effective in preventing violent drinking, hangover and hangover.

  Alcohol consumption can accumulate acetaldehyde, which can be associated with headaches, nausea, tremors and dizziness. This is usually called a hangover. Several products are known in the art that can reduce hangover symptoms when taken. Examples of such products are fructose-caffeine-vitamin C mixtures and fructose-caffeine mixtures. Such products are generally in the form of powders or tablets and are added as water to be rehydrated. These products always contain analgesics such as paracetamol and aspirin to reduce pain. Products containing antihistamines such as Zyrtec are also often used to reduce the symptoms of hangover. However, it may not be desirable to use analgesics or antihistamines in this way. For example, it may exacerbate problems associated with alcohol consumption, such as gastrointestinal bleeding.

  WO9961038 is an example of such a product and contains some of the ingredients used in the present invention. The composition described in WO9961038 includes a nutritionally beneficial substitute and a substitute that stimulates short or long term psychological feedback, and a nutritionally beneficial substitute A vehicle or device for delivering an article to a recipient is claimed. This composition is not formulated to promote alcohol metabolism and also contains some ingredients that have already been shown to strongly inhibit alcohol metabolizing enzymes. This is especially the case for thiol compounds such as cysteine, acetylcysteine, glutathione and methionine [1], which inhibit the activity of liver alcohol dehydrogenase (LADH) (μM to mM Ki). This is also true for some heterocyclic reagents in this composition [2, 3].

  More importantly, the composition described in WO9961038 also lacks at least three components most important for the alcohol metabolism promoting action of the present invention. These are Yerba Mate, Eleutherococcus senticoccus, Glycyrrhiza grabra. These are essential ingredients in a synergistic combination that provides stimulation to alcohol and acetaldehyde metabolic enzymes. Experiments have shown that the absence of each of these components reduces the synergistic and overall effects by 30-50% and 15-25%, respectively. It should be noted that mate tea is added not only to contain natural caffeine, but also to contain several other active ingredients listed in Table 1.

  WO 98/32434 describes a new acetaminophen analgesic composition aimed at reducing liver toxicity and eliminating hangover, which composition comprises aspartic acid and acetaminophen which promote alcohol metabolism. Contains methionine to alleviate liver toxicity.

  British Patent No. 2308810 describes a composition containing fructose and no analgesics for replenishing dehydrated patients with water or preventing dehydration. This composition is also claimed to treat hangover, physical exhaustion, or diarrhea caused by dehydration by preventing dehydration.

  Japanese Patent No. 0601474 describes a product that contains glucoside of quercetin, a divalent metal ion and liquorice extract as active ingredients and can promote alcohol metabolism.

  The novelty of the present invention over the prior art resides in combining specific ingredients that act synergistically as described above. In particular, the combinations of mate tea, Panax ginseng, ginkgo biloba, eleuterococcus, ginger and Glycyrrhiza glabra (Liquorice Root). Some of these components can be found in the prior art described above, but are not in the combination necessary to obtain a significant synergistic effect. The novel combination of the present invention has been found through numerous inclusion / non-containment experiments. As a result of these experiments, surprisingly, a particularly effective combination for preventing hangover (and increasing energy level) is mate tea, ginseng and ginkgo, whose synergistic effect is just an additive effect Turned out to be much larger. Another novel combination is Eleuterococcus, ginger and Grukylliza grubra (licorice), which have been found to significantly increase the activity of alcohol metabolizing enzymes.

  A highly specific composition is provided that degrades alcohol and acetaldehyde much faster than any of the products described above and existing fructose-vitamin C and fructose-caffeine mixtures. This composition does not contain enzymes that impair the stability of the product or NADH / NAD (nicotinamide, adenine, dinucleotide) and does not contain compounds that are harmful to health. Caffeine varieties, herbs and fructose are synergistic.

  It is an object of the present invention to obviate the above disorders by promoting the metabolism of alcohol and acetaldehyde, thereby providing a composition suitable for preventing and reducing alcohol related disorders and hangover symptoms. Or to alleviate.

  The present invention is a stable composition, preferably a soft drink, that promotes the degradation of alcohol and acetaldehyde in the body, including a synergistic combination of caffeine, herbs and fructose, and preferred embodiments include caffeine, guarana Caffeine, mate tea, eleuterococcus, ginseng, ginger, grukyrriza grabra (licorice), fructose and additional ingredients (sugar, flavoring, coloring, vitamins, stabilizers, whole fruit powder, etc.) And include ginkgo as needed.

  The present invention is a stable composition, preferably a soft drink, that promotes the breakdown of alcohol and acetaldehyde in the body, including a synergistic combination of caffeine, herbs and fructose.

  The present invention is used, for example, to reduce and prevent the occurrence of various symptoms associated with an individual's hangover. The blood concentration of alcohol can also be reduced by taking the composition of the present invention the day after alcohol consumption. This composition also partially reduces and prevents dehydration. In order to prevent the occurrence of various symptoms associated with hangover, this composition can be taken immediately after alcohol consumption. By promoting the action of key enzymes in alcohol metabolism, the degradation of alcohol and acetaldehyde is promoted, and adverse effects due to excessive alcohol consumption (eg, headache, cardiovascular disorders, dry mouth, nausea, tremors, dizziness, fatigue and coordination) Failure (coordination differences) is suppressed.

Therefore, the present invention
-Reduce or prevent the occurrence of symptoms associated with hangover;
Providing a composition suitable for use in accelerating the degradation of alcohol and in reducing and preventing dehydration.

  The compositions of the present invention can also be taken to increase an individual's vitality after physical exhaustion due to exercise or illness. Individuals who travel for a long time, such as over long distances, may become dehydrated using physical strength, especially due to alcohol consumption. Therefore, taking this composition can also provide a medicinal effect.

The composition of the present invention can also be used in the following several medical applications.
-Treatment of acute alcoholism.
-Since the degradation rate of alcohol (and acetaldehyde if possible) can be increased, it can also be used to suppress cell and tissue damage caused by these highly reactive substances.
-This composition is also suitable for suppressing alcohol dependence of alcoholic because it can reduce the toxic effects of ethanol.
If the alcohol degradation acceleration exceeds the acetaldehyde degradation acceleration, the present invention can also be used to enhance the effect of a drug such as disulfiram. Furthermore, side effects and drug toxicity can be suppressed and eliminated by reducing the required drug dose.

  The compositions of the present invention may also contain some additional ingredients such as green tea, additional sugars, flavorings, colorants, vitamins, stabilizers, whole fruit powders. An analgesic can also be added to the composition.

  Preferably, the composition dissolved in water or other suitable liquid can be made foamable, typically by carbonation, for example with carbon dioxide. The composition can also be formulated in the form of dry powders, mixtures, syrups, granules, tablets and sachets. The composition of the present invention can also be formulated into a drug. Where appropriate, the drug further comprises a pharmaceutically compatible carrier. Suitable carriers and the formulation of such agents are known to those skilled in the art.

Composition The amount of each component of the composition of the present invention is individually selected depending on the particular application in which the composition is used. In a preferred embodiment of the invention, the composition comprises caffeine (0.001-0.1%, preferably 0.01%), guarana caffeine (0.001-0.1%, preferably 0). 0.01%), mate tea (0.001-0.1%, preferably 0.01%), eleuterococcus (0.05-2.0%, preferably 0.2%), ginseng (0.0. 002-0.2%, preferably 0.02%), ginger (0.3-30%, preferably 3.0%), Grukylliza grabra (licorice) (0.02-2.0%, preferably 0.2%), ginkgo (0.00-0.2%, preferably 0.02%) and optionally fructose (0-99%, preferably 75%), additional ingredients (sugar, flavoring) , Colorants, vitamins, stabilizers, whole fruit powders, etc.) (0.1-8 .5%, preferably 21.5%). All the above percentages are percentages by dry weight of the composition.

  This composition is preferably provided as an aqueous composition by dissolving it in water or other suitable liquid. Preferably, the composition is dissolved in a ratio of 1 part composition to 10 parts water / suitable liquid, more preferably 1 part composition to 5 parts water / suitable liquid. Usually, the preferred amount of this aqueous composition for an individual is 250 to 750 ml, more preferably 400 to 500 ml. The pH of this aqueous composition is about 3 to 7.5, more preferably 3 to 5.5.

Methods are provided for producing the compositions of the present invention. The method of the present invention comprises:
a) mixing fructose and water soluble dry ingredients (ie caffeine, eleuterococcus and glucillriza grabra (licorice)),
b) adding water to the dry mixture of a) in the ratio 1: 2 (dry mixture: water);
c) stirring the mixture until all components are dissolved;
d) adding ingredients (guarana, mate tea, ginger, ginseng and, if necessary, ginkgo),
e) stirring the mixture until a homogeneous mixture is obtained;
f) adding fragrances, flavorings and / or stabilizers,
g) diluting the mixture with water (if necessary) until an arbitrary amount is obtained, and if necessary,
h) adding a coloring component to the mixture obtained in a) to e) and / or
i) adding a gas, preferably carbon dioxide, to impart foamability to the mixture obtained in a) to e).

Mechanism of Action The basic pathway of ethanol metabolism [4] is shown in FIG. Table 2 shows the effect of the composition on ethanol degradation stimulation and hangover prevention. A comparison between the present invention (Table 2A) and fructose-caffeine-vitamin C beverage (Table 2B) is also shown in Table 2. The effect of this composition in each case examined was that alcohol degradation was accelerated by 40-90% and hangover symptoms were significantly reduced. The accelerated alcoholysis is probably due to the enzyme-NADH (the enzyme-NADH-activator (ERA) ternary complex formed by caffeine varieties and / or herbs being a general rate-limiting step. This is because it is more unstable than dissociation of (ER). The possible mechanism is almost the same as the previously reported mechanism for 2,2′- and 4,4′-dipyridyl [5]. The promotion of alcohol degradation is partly due to the stimulation of catalase and / or CYP2E1, which is also involved in alcohol metabolism [6].

  Since accumulation of acetaldehyde is a major cause of hangover symptoms [7, 8], the effect of this composition on hangover also indicates that aldehyde dehydrogenase activity was stimulated. One way to promote acetaldehyde degradation can be by stimulating LADH, which can also oxidize aldehydes [9].

  The effect of fructose on ethanol metabolism has been debated for decades. The conclusion about this effect may be different due to differences in experimental design [10]. Numerous studies have shown that fructose alone can stimulate ethanol degradation, but the effect of the above composition is due to the synergistic effect of sugar and other activators. This is also shown by the results in Table 2, where the effect of fructose-caffeine-vitamin C is much less than that of the present invention. The effect of fructose is probably due to the ability to accelerate ATP turnover and create more ADP available for NADH reoxidation (FIG. 3). Since NADH is a potent inhibitor of LADH (Ki = 56 μM) [6], promoting NADH reoxidation may result in weaker inhibition of LADH activity.

  The novelty of the present invention over the prior art resides in a combination of ingredients that work synergistically. This is especially the case for yerba mate, ginseng, ginkgo, eleuterococcus, ginger and gurukiriza grabra. Some of these components can also be found in the prior art, but they have not been combined to obtain a significant synergistic effect. The novel combination of the present invention has been found through numerous inclusion / non-containment experiments. The results of these experiments surprisingly show that mate tea, ginseng and ginkgo are particularly effective combinations to prevent hangover (and increase vitality), and their synergistic effects are much greater than just cumulative effects. There was found. Another novel combination is Eleuterococcus, ginger and Grukylliza grubra (licorice), which have been found to significantly increase the activity of alcohol metabolizing enzymes.

  From the examples and the experimental results in Table 2, fructose-caffeine-vitamin C drink can promote alcohol metabolism to some extent and reduce hangover symptoms, but the effect of the present invention is much greater in all matters. It has been shown.

  A particularly preferred formulation of an analgesic additive-free composition embodying the present invention is: 35 mg caffeine, 28 mg guarana caffeine, 27 mg mate tea, 360 mg eleuterococcus, 70 mg ginseng, 360 mg gurukirisa gurabra (licanthus), 1 g ginger And 90 g of fructose. Natural orange flavor is then added and the composition is diluted with water to a total volume of 500 ml. This solution is then carbonated to the final composition. It has been found that when this composition is taken 30-60 minutes after alcohol consumption, alcohol degradation is accelerated and is particularly effective in preventing and reducing symptoms associated with hangover.

The trials shown in Tables 2 and 3 involved 10 individuals (6 men and 4 women aged 24 to 57 years).
-In the first study (Table 2A), the investigator was given 8 ounces (about 2.4 dl) of vodka divided by 6 dl of the Sprite (The Coca Cola Company). This alcohol was consumed within 1 hour. 45 minutes after alcohol consumption, each person drank 500 ml of water. The alcohol concentration was then measured as follows. One week later, the same study was given the same amount of sprite split vodka. 45 minutes after alcohol consumption, each person drank 500 ml of the composition of the present invention. The alcohol concentration was then measured as follows.
In the same way as described in the test of Table 2A, except that the investigator was given 500 ml of a solution containing 90 g of fructose, 90 mg of caffeine and 500 mg of vitamin C instead of the composition of the invention. Both (Table 2B) were performed. The alcohol concentration was remeasured as follows.

  The alcohol concentration was measured every 30 minutes (measured in ° / oo) in each experiment using a CA 2000 Digital Alcohol Detector. Each value is an average of 4 parallel measurements. Evaluation of the effect on hangover was graded on a scale of 1 to 10 (10 being the highest score).

Results The results of the first test are shown in Table 2A. In each case, taking 500 ml of the composition of the present invention significantly promoted alcohol degradation. This increment was 67-92% with an average of 83%. The hangover symptoms graded on a scale of 1-10 (corresponding to 10-100% reduction of hangover symptoms) were also significantly reduced (80-100%).

  As a result of the comparative study (Table 2B), after taking the fructose-caffeine-vitamin C beverage, the increase in alcohol degradation and reduction of hangover symptoms was much slower than that. The alcohol degradation increment was 29-56%, with an average of 45%. The reduction in hangover symptoms was 50-70%.

  It is clear from the above results that the composition of the present invention is a particularly effective combination that prevents hangover (and increases vitality). This effect worked synergistically and was much greater than a mere cumulative effect.

  It is easy to modify the above embodiment to include antibacterial agents, vitamins, colorants and the like. It can also be formulated with natural effervescent spring water to eliminate the need for carbonation of the composition. The composition is provided as an orange beverage that promotes alcohol breakdown and reduces hangover. Another formulation for citrus beverages, lemon beverages and lime beverages contains approximately equal amounts of the same major ingredients as above, but different flavors / colorants.

  Although the present invention has been described with reference to specific embodiments thereof, it should be apparent to those skilled in the art that various modifications of the composition and / or other applications are possible.

The amount of the composition described in the experimental examples using the fructose-free composition is relatively high. This is due to the fructose content. Therefore, a new set of experiments was performed to minimize the amount of composition required.

  Using the same conditions as described in the previous experiment (and Table 2), the same investigator was given the following: caffeine 5 mg, guarana caffeine 85 mg, mate tea 10 mg, eleuterocox 360 mg, ginseng 70 mg, glucillrisa grabra ( 2 cm of a composition containing 360 mg of licorice, 100 mg of ginkgo biloba and 1 g of ginger.

  This composition was found to accelerate alcohol degradation by an average of 60% as shown in Table 3 when taken 30 minutes after alcohol consumption. From this result, it can be seen that the contribution ratio of fructose to alcohol decomposition promotion is about 20-25%. This is in good agreement with the previously reported result [10].

This new composition has several advantages compared to the fructose-containing composition, although the overall effect on alcohol degradation is somewhat reduced. That is,
-The amount is considerably reduced, making it very easy to take. This can be particularly important in the case of acute alcoholism.
-No adverse effects caused by consuming high doses of fructose.
-There is no long-term adverse effect of fructose on the liver.
-Patients who do not accept fructose can also use this composition to obtain a medicinal effect.

  In summary, these advantages make the fructose-free composition of the present invention the most preferred composition. However, depending on the desired taste and / or amount, fructose can be added as a sweetener or to enhance the effect of alcohol degradation.

Table 1: Composition of mate tea.
By analysis, mate tea has the following composition:
Water, cellulose, gum, dextrin, mucus, glucose, pentose, fatty substance, aromatic resin, legumin, albumin, xanthine, theophylline, trigonelin, folic acid, caffeic acid, virigic ( viric) acid, chlorophyll, cholesterol and essential oil.
Ash contains a large amount of potassium, lithium, folic acid, sulfuric acid, carbon acid, hydrochloric acid and citric acid, as well as trace amounts of magnesium, manganese, iron, aluminum and arsenic.
Xanthine, theophylline and theobromine are the three closely related alkaloids contained in mate tea and belong to the most interesting compounds for treatment. The average amount of xanthine in mate tea is estimated at 1.60% and 1.10% in decoction.

Table 2: Effects of the composition of the invention on alcohol metabolism and hangover symptoms.
Alcohol was consumed by drinking vodka mixed with sprite (The Coca Cola Company) within 1 hour. The alcohol concentration (measured in ° / oo) was measured every 30 minutes with a CA 2000 Digital Alcohol Detector. Each value is an average of 4 parallel measurements. Evaluation of the effect on hangover was graded on a scale of 1 to 10 (10 being the highest score). Ten healthy individuals, six men and four women, participated in the study.
A) 500 ml of the composition according to the invention was consumed 30-60 minutes after consumption of the alcohol.
B) 30-60 minutes after consumption of alcohol, 500 ml of a solution containing 90 g of fructose, 90 mg of caffeine and 500 mg of vitamin C was consumed.

Table 3: Effect of a composition without fructose on alcohol metabolism and hangover symptoms.
The composition 2cl without fructose was consumed 30 minutes after alcohol consumption. The experimental procedure is the same as in Tables 2A and B.

(References)
1) Langland, B .; T. T. et al. Morris, D .; L. And McKinley-McKee, J. et al. S. (1999) Comp. Biochem. Biophys. Part B, 123, 155-162.
2) Boyer, P .; D. (Ed). Enzymes, Volume XIA, 3rd edition New York and London. Academic Press; Brandon, C .; I. Jonvall, H .; Eklund, H .; Furugren, B .; (1975) Alcohol Dehydrogenases.
3) Miwa, K .; Okuda, H .; Ogura, K and Tadashi, W .; (1987) Biochem. Biophys. Res. Com. 142, 993-998.
4) Kennedy, N .; P. And Tipton, K .; F. (1990) Essays in Biochem. 25, 137-194.
5) Langland, B .; T. T. et al. And McKinley-McKee, J. et al. S. (1997) Comp. Biochem. Physiol. 117, 56-61.
6) Lands, W .; E. M.M. (1998) Alcohol. 15, 147-160.
7) Kitson. T. T. et al. M.M. (1977) Journal of Studies on Alcohol. 38, 96-113.
8) Langland, B .; T. T. et al. And McKinley-McKee, J. et al. S. (1996) Alcohol and alcohol intoxication (Alcohol & Alcoholism). 31, 75-80.
9) Henehan, G .; T. T. et al. M.M. And Openheimer, N .; J. et al. (1993) Biochemistry. 32, 735-738.
10) Cronower, B.M. P, et al. (1986) The Journal of Pharmacology and Experimental Therapeutics. 236, 574-579.

Basic pathway of ethanol metabolism. Alcohol is converted to acetaldehyde by three enzymes: alcohol dehydrogenase, catalase and CYP 2E1. Acetaldehyde is converted to acetate by aldehyde dehydrogenase. Recommended mechanism for stimulation of alcohol and / or acetaldehyde degradation. Stimulation with an activator that forms an enzyme-NADH-activator ternary complex which is more unstable than the normal rate-limiting enzyme-NADH product dissociation. E = enzyme; liver alcohol dehydrogenase or aldehyde dehydrogenase O = NAD (oxidized form of coenzyme) S = substrate; alcohol or acetaldehyde P = product; acetaldehyde or acetate R = NADH (reduced coenzyme) A) activator; caffeine variant and / or herb k ₃ = rate limiting step Interaction between ethanol metabolism by LADH and mitochondrial respiration. Ethanol is oxidized to acetaldehyde by LADH (a) and NAD is simultaneously reduced to NADH. NADH is then reoxidized to NAD in mitochondria (c) by the electron transport chain (d) and oxygen is consumed (g). Substrates that are phosphorylated at the same time as ADP is formed from ATP (f) increase electron flow through the respiratory chain (e), followed by increased oxygen consumption and NADH reoxidation rate.

Claims (11)

  A composition for human consumption comprising caffeine, guarana caffeine, yerba mate, eleuterococcus, ginseng, ginger, glucillriza grabra, ginkgo and fructose.   The composition of claim 1 comprising an analgesic.   Composition as a percentage of dry weight, caffeine (0.001-0.1%, preferably 0.01%), guarana caffeine (0.001-0.1%, preferably 0.01%) ), Mate tea (0.001 to 0.1%, preferably 0.01%), eleuterocox (0.05 to 2.0%, preferably 0.2%), ginseng (0.002 to 0) 0.2%, preferably 0.02%), ginger (0.3-30%, preferably 3.0%), Grukylliza grubra (licorice) (0.02-2.0%, preferably 0.2 %), Ginkgo (0.00-0.2%, preferably 0.02%) and optionally fructose (0-99%, preferably 75%), from claim 1 to claim 2 Not included in alcohol and / or acetaldehyde An additional component that does not inhibit the activity of the enzyme (sugar, flavor, colorant, vitamin, stabilizer, whole fruit powder, etc.) (0.1-89.5%, preferably 21.5%). Or the composition of 2.   The composition according to any one of claims 1 to 3, comprising green tea.   Use of a composition according to any one of claims 1 to 4 which promotes the degradation of alcohol and acetaldehyde.   The composition according to any one of claims 1 to 5, wherein the composition can be formulated as a beverage, syrup, dry powder, tablet, granule or sachet.   The aqueous product according to any one of claims 1 to 6, wherein a compound is added to make the product foamable.   The aqueous product according to any one of claims 1 to 7, wherein the product is made foamable by carbonation.   The pharmaceutical product according to any one of claims 1 to 8. a) mixing fructose and water soluble dry ingredients (ie caffeine, eleuterococcus and glucillriza grabra (licorice)),
b) adding water to the dry mixture of a) in the ratio 1: 2 (dry mixture: water);
c) stirring the mixture until all components are dissolved;
d) adding ingredients (guarana, mate tea, ginger, ginseng and, if necessary, ginkgo),
e) stirring the mixture until a homogeneous mixture is obtained;
f) adding fragrances, flavorings and / or stabilizers,
g) diluting the mixture with water (if necessary) until an arbitrary amount is obtained, and if necessary,
h) adding a coloring component to the mixture obtained in a) to e) and / or
A method for producing an aqueous product according to any one of claims 1 to 5, comprising i) adding a gas, preferably carbon dioxide, to impart foaming properties to the mixture obtained in a) to e). .   Accelerate the decomposition of alcohol and acetaldehyde to suppress adverse effects (eg, headache, cardiovascular disorders, dry mouth, nausea, tremors, dizziness, fatigue and coordination disorders) caused by excessive alcohol consumption, and the occurrence of symptoms associated with hangover Use of a composition according to any one of claims 1 to 9 in the manufacture of a product to prevent

Images