WO2024253632A1 - Composite eugeroic - Google Patents

Abstract

The invention relates to medicine, and more particularly to nutritional science and pharmaceutics, and even more particularly to a composition for alleviating tiredness and fatigue. A composite eugeroic contains amino acids or derivatives thereof selected from the group consisting of: dextrorotatory, levorotatory or racemic tyrosine, dextrorotatory, levorotatory or racemic histidine, dextrorotatory, levorotatory or racemic acetyltyrosine, dextrorotatory, levorotatory or racemic acetylhistidine, 2-methyl-guanidinoacetic acid (creatine) or phosphorous derivatives thereof in the form of pharmaceutically acceptable salts. The technical results include a significant eugeroic effect, increased wakefulness and ability to work, rapid action, and a broadening of the existing range of effective drugs for preventing tiredness or fatigue.

Description

COMPOSITE AGENT-EUGEROIC

The invention relates to medicine, in particular to nutritional science and pharmaceuticals, namely, to the composition of a composition for relieving fatigue and tiredness.

The concept of "Fatigue" is defined as a state of the body in which the physiological processes of the body cannot be maintained at a level sufficient for normal functioning due to excessive load for a given process or, in other words, the organs cannot maintain a given intensity of physical or mental load [Lebedev M.A., Palatov S.Yu., Kovrov G.V. RMZh. Medical Review. Vol. 22, No. 4, 2014, pp. 4-7].

It is important to distinguish between the concept of “fatigue” and the concept of “fatigueability”.

Fatigue is a symptom complex accompanying tiredness, its, figuratively speaking, "business card", manifested by a feeling of weakness, lethargy, impotence, drowsiness, combined with a feeling of physical and mental discomfort, decreased physical and mental performance, changes in mood and quality of life. Fatigue syndrome can occur as a result of overexertion, and also develop and last chronically. In the latter case, this condition requires long-term complex treatment. In contrast, fatigue due to overexertion is a physiological process and disappears after proper and sufficient rest.

Physiologically, fatigue is classified as central nervous system fatigue, neuromuscular junction fatigue, and peripheral limb fatigue. Fatigue is a complex physiological process that includes many physiological and biochemical factors, and this normal physiological phenomenon inevitably occurs at a certain stage of mental activity or physical activity of the body. This means a temporary decrease in the initial performance of the body and is a sign that the body needs rest [Lebedev M. A., Palatov S. Yu., Kovrov G. V. RMZh. Medical Review. Vol. 22, No. 4, 2014, pp. 4-7].

But sometimes there are situations when, when tired, the body requires the use of special means to delay rest, but while ensuring optimal performance of the body. In this case, it is necessary to eliminate the symptoms characteristic of fatigue: drowsiness, lethargy, weakness, decreased concentration attention and a decrease in the speed of task completion.

However, there is no available drug or food product on the market today to relieve fatigue that is significantly effective and safe to use.

There are known drugs that reduce the feeling of fatigue, such as psychostimulants. A typical representative is phenamine (amphetamine) [Heal, David J; Smith, Sharon L; Gosden, Jane; Nutt, David J. Amphetamine, past and present - a pharmacological and clinical perspective bnrnnZ of Psychopharmacology. 27 (6): 479-496. doi: 10.1177/0269881113482532].

Its use gives a fairly pronounced tonic effect, as a rule, tired people feel a surge of strength and energy when using it, the need for sleep and rest can be delayed for up to 12 hours. But the use of phenamine and similar drugs is limited due to side effects, the most serious of which is addiction, the development of dependence. But what is even more important is that after its use, proper and long-term rest is necessary, otherwise serious complications may occur, such as myocardial infarction or stroke. Also, a common side effect is palpitations and arrhythmia, even fatal. All this limits the use of phenamine and drugs similar to it in structure and effect [Westover, Arthur N.; Halm, Ethan A. "Do prescription stimulants increase the risk of adverse cardiovascular events? A systematic review". BMC Cardiovascular Disorders. 12: 41. doi:10.1186/1471-2261- 12-41].

Almost all stimulants of the amphetamine type, in one way or another, change the metabolism and effects of the main neurotransmitters in the brain: dopamine, norepinephrine, serotonin, histamine, methyl-d-aspartate, etc. In this case, the balance in their effects and action on the corresponding receptors is often disturbed, which often causes mental problems [Baicy K, Bearden CE, Monterosso J, Brody AL, Isaacson AJ, London ED (2005). "Common substrates of dysphoria in stimulant abuse and primary depression: therapeutic targets". Int Rev Neurobiol. International Review of Neurobiology. 65: 117-45. doi:10.1016/S0074-7742(04)65005-7].

Another class of drugs are eugeroics, i.e. drugs against drowsiness as an extreme manifestation of fatigue. A representative of this group is modafinil. Its use leads to an improvement in concentration, determination, memory and other mental abilities; a decrease in drowsiness; an increase in performance; as well as a decrease in appetite and a decrease in food consumption [Y. In, K. Tomoo, T. Ishida, Y. Sakamoto: Crystal and Molecular Structure of an (S)-(+)- Enantiomer of Modafinil, a Novel Wake-Promoting Agent. In: Chem. Pharm. Bull. 52, 2004, S. [1186-1189].

But the use of modafinil is accompanied by a number of common side effects. In particular, when using the drug, the most common side effects are insomnia, headache, loss of appetite. Simultaneous use of modafinil with alcohol and other psychoactive drugs can lead to death. With prolonged use of the drug and its sudden cancellation, modafinil withdrawal syndrome develops.

Therefore, it is a widely used drug in clinical practice with clear indications for use, but for everyday life, caffeine and its derivatives are used to increase alertness and reduce the manifestations of fatigue.

Caffeine is a natural substance that exhibits its effect precisely when nervous system fatigue develops and is widely used to temporarily increase performance. Its action is associated with competitive antagonism with a neurotransmitter substance in the brain that accumulates during fatigue - adenosine. Caffeine, by blocking the brain's receptors to adenosine, delays the development of the sensation of the brain "falling asleep". But the effects of caffeine are transient, and repeated use, as a rule, does not give the desired result due to the effect on the feeling of fatigue, but increases the risk of developing side effects in the form of palpitations, arrhythmia, irritability, aggressiveness, anxiety and even convulsions, but since it is contained in coffee and tea, it is consumed by most people in the world and is the most widely used substance for fatigue and its symptoms [Jamieson RW. "The essence of commodification: caffeine dependencies in the early modem world". Journal of Social History. 35 (2): 269-294. doi:10.1353/jsh.2001.0125].

Despite such popularity, its use even in relatively large doses is often insufficiently effective, on the one hand (consider the developing tolerance to it), and on the other hand - it can cause serious side effects, especially if the recommended doses are exceeded, and usually this is no more than 400 mg per dose. In addition, the disadvantages of using caffeine as a means of increasing vigor in case of fatigue is the slow onset of the effect, which in the best case is achieved in about 1 hour. It is possible to quickly achieve the effect by injecting into a muscle or vein, but this requires certain skills and cannot be used routinely.

Therefore, attempts are constantly being made to enhance and speed up the effects of caffeine and reduce its side effects.

For this purpose, it has been proposed to introduce caffeine in the form of chewing gum, in the form of a composition with ingredients that mask the bitter taste of caffeine. This provides an improved chewing gum composition containing caffeine. The chewing gum composition contains a specific particle size distribution of caffeine to reduce the perception of bitterness of traditional caffeine gums. In addition, the present invention provides methods for mixing a chewing gum composition with caffeine, which also reduce bitterness by selecting caffeine, wherein the caffeine has a particle size distribution of about 0.0% by 40 mesh, about 1-20% by 60 mesh, about 5-30% by 80 mesh and at least about 50% by 80 mesh. processing time and sequence for mixing the various ingredients. A chewing gum composition comprising a water-insoluble base portion, a water-soluble portion and caffeine, wherein the caffeine has a particle size distribution of about 0.0% by 40 mesh, about 1-20% by 60 mesh, about 5-30% by 80 mesh and at least about 50% by 80 mesh. The small particle size of caffeine in combination with the sweeteners acesulfame and gluconolactone makes this gum palatable and ensures the release of caffeine into the oral cavity [US 6024988 A, A23G 4/06, A23G 4/068, A23V 2002/00, published 15.02.2000].

But this gum did not become widespread because it left a bitter aftertaste that was difficult to remove.

A nutraceutical composition of caffeine with theanine is also known. The embodiment of this invention provides compositions or mechanisms for oral administration of caffeine using a functional nutraceutical confectionery composition. According to various embodiments, the nutraceutical confectionery composition is provided with a ratio of caffeine to L-theanine in the range of from about 1:1 to about 1:2. In various embodiments, the nutraceutical confectionery composition can contain caffeine in the range of from about 5 mg to about 100 mg per serving. L-theanine can be provided in the range of from about 5 mg to about 200 mg per serving. In an embodiment, a method of treatment for increasing energy and alertness while maintaining relaxation and concentration is provided. The method includes orally administering to an individual a nutraceutical confectionery composition containing caffeine and L-theanine in combination with a nutraceutically acceptable carrier such that caffeine and L-theanine are absorbed through the oral mucosa of the individual. A variant of the confectionery composition is chewing gum, which allows for the release of ingredients into the oral cavity. This allows for enhancing and accelerating the effects of caffeine [US 10441535 B2, IPC: A61K 9/68, A23K 31/198, A23K 31/522, A23G 4/06, A61G 4/12, A61G 4/14, A23L 33/105, A23L 33/175, A61K 9/20, publ. [15.10.2019].

The invention, briefly described below, provides a healthy alternative in beverages that provide energy and focus and that feature increased availability of beneficial nutrients. In addition, a source of choline is used (citicoline is particularly useful) and is surprisingly effective even at low levels (or even in the absence) of caffeine in increasing energy levels in subjects who drink these compositions. The energy composition of this embodiment comprises a relatively low concentration of methylated xanthine, a choline derivative, and at least one flavoring agent in an amount sufficient to make the energy composition palatable. In another embodiment of this embodiment, the energy composition further comprises one or more amino acids or amino acid derivatives. Examples of amino acids or derivatives thereof include, but are not limited to, N-acetyl L-tyrosine, L-phenylalanine, taurine, and combinations thereof. In a particular case, the amino acids or derivatives thereof are present in an amount of from about 0.005 to about 0.05 g/mL. In a particular case, the amino acids or derivatives thereof are present in an amount of from about 0.01 to about 0.03 g/mL. In another particular case, the amino acids or derivatives thereof are present in an amount of from about 0.0125 to about 0.025 g/mL.

In a particular case, N-acetyl L-tyrosine is present in an amount of from about 0.001 to about 0.01 g/mL. In a particular case, N-acetyl L-tyrosine is present in an amount of from about 0.002 to about 0.009 g/mL. In another particular case, N-acetyl L-tyrosine is present in an amount of from about 0.003 to about 0.007 g/mL.

In a particular case, L-phenylalanine is present in an amount of about 0.001 to about 0.008 g/ml. In a particular case, L-phenylalanine is present in an amount of about 0.002 to about 0.007 g/ml. In another particular case, L-phenylalanine is present in an amount of about 0.003 to about 0.007 g/ml [RU 2487645 C2, IPC: A23L 2/38, published 20.07.2013, Bulletin No. 20].

This composition is proposed for use in beverages, which can speed up the entry of nutrients and stimulants into the blood. Somewhat surprising is the presence of the sulfur-containing amino acid taurine in this composition. After all, it has been widely known since the 1980s that taurine is an inhibitory neurotransmitter acid [Simo S. Oja, Pirjo Saransaari. Pharmacology taurine. In Handbook of Neurochemistry and Molecular Neurobiology [electronic resource]: Amino Acids and Peptides in the Nervous System. Publisher: Boston, MA: Springer US, 2007. Description: digital. ISBN: 9780387303734; Fang. Ju Lin, Michael M Pierce, Amita Sehgal, Tianyi Wu, Daniel C Skipper, Radhika Chabba Effect of taurine and caffeine on sleep-wake activity in Drosophila melanogaster. Nat Sci Sleep. 2010; 2: 221-231. Published online 2010 Sep 24. Doi: 10.2147/NSS.S13034. PMCID: PMC3630960PMID: 23616711].

The results presented in this article show that treatment with taurine at concentrations of 0.1% to 1.5% reduces motor activity by 28%-86% and shifts it from daytime to nighttime. 0.75% taurine "increases total sleep by 50%. These results indicate that taurine improves sleep, whereas caffeine has been previously reported to decrease sleep, so they cancel each other out, which is not a useful combination in an energy mix.

The combination of caffeine with certain amino acids does have a potentiating effect.

It is known that the use of caffeine with tyrosine and theanine, even with a single use, improves vigor, performance and the ability to solve problems when tired [Javier Zaragoza, Grant Tinsley, Lem Taylor. Effects of acute caffeine, theanine and tyrosine supplementation on mental and physical performance in athletes. Journal of the International Society of Sports Nutrition volume 16, Article number: 56 (2019)]. But theanine is also an inhibitory substance, so the effect of a combination of caffeine with tyrosine could possibly be even better. Therefore, it is clear that there is a need for further search for natural substances that can enhance the effects of caffeine on fatigue. The authors postulate the concept of searching for substances that could affect the brain through receptor mechanisms, as well as directly affect metabolism. Only amino acids can be such substances. Therefore, the above-described invention was taken as a prototype. But unlike the prototype, the authors concentrated their search on a combination of amino acids that affect the synthesis of stimulating neurotransmitters. The authors unexpectedly found that a combination of these amino acids could enhance the effects of caffeine in conditions of fatigue.

The invention was based on the task of creating a composite eugeroic agent by selecting components, which would have a significant eugeroic effect and contribute to increased vigor and performance, would have a rapid effect, and would also expand the range of effective means for the prevention of fatigue and tiredness.

The stated problem is solved in that the composite eugeroic agent based on amino acids, according to the invention, contains amino acids or their derivatives, selected from the group: dextrorotatory, levorotatory or racemic tyrosine, dextrorotatory, levorotatory or racemic histidine, dextrorotatory, levorotatory or racemic acetyltyrosine, dextrorotatory, levorotatory or racemic acetylhistidine, 2-methylguanidine aminoacetic acid (creatine) in the form of pharmaceutically acceptable salts.

An additional difference is that for every 1 mass fraction of tyrosine there are from 0.2 to 5 mass fractions of histidine and creatine.

The second additional difference is that for every 1 mass fraction of tyrosine there is additionally from 0.2 to 1 mass fraction of a psychostimulant.

A third additional difference is that the psychostimulant is caffeine in the form of a pharmaceutically acceptable salt or its plant equivalent.

The fourth additional difference is that the psychostimulant is modafinil or its derivative in the form of a pharmaceutically acceptable salt.

One of the options for producing the composition is to make it in the form of an effervescent tablet.

Another embodiment of the composition is its use in the form of lozenges, with a different composition of excipients, where in one embodiment of the invention the tablet is a lollipop.

A possible option for making the composition is to use it in the form of a solution or drink.

Such a composition, as will be shown in the examples, exhibits a significant eugeric effect and helps to increase vigor and performance in general, and the use of the lozenge form accelerates its action, since the composition, when used in this way, releases substances into the oral cavity, from where they are absorbed very quickly.

The list of effective means for preventing fatigue and tiredness has also been expanded.

The production of such compositions, according to the invention, will not be difficult for a person skilled in the art.

The manufacturing stages include calculating the required quantities of components, mixing them until a homogeneous mass is obtained, for example using a "drunk barrel" mixer, adding substances to the mixture that ensure the mass is tableted, mixing them, feeding them to the tableting device, followed by the pressing stage, preliminarily, if necessary, moistening and granulating the mass for tableting. The resulting tablets are packed in primary packaging. In the case of making a lollipop, first provide its base in the form of a caramelized sugar base; form a first mixture by combining the sugar base with caffeine, histidine, natural flavors, and stabilizers if necessary; form a second mixture by combining caffeine, tyrosine, creatine, sorbitol, add the first portion to the second, mix them, heat them and pour into the cells of the matrix, followed by cooling and solidification of the mass and pushing the tablet out of the matrix.

Examples of implementation of the composition according to the invention.

Example 1.

Tyrosine - 500 mg;

Histidine - 500 mg;

Creatine - 500 mg;

Caffeine citrate - 50 mg;

Tabletose - 230 mg;

Aerosil - 50 mg;

Calcium stearate - 10 mg.

Example 2.

Acetyl-Tyrosine - 500 mg;

Acetyl-Histidine - 500 mg;

Creatine - 500 mg;

Caffeine citrate - 50 mg;

Sorbitol - 130 mg;

Caramel sugar - 8,000 mg;

Flavoring agent

Ethylparaben - 0.05 mg

Example 3.

Acetyl-Tyrosine - 500 mg;

G istidine - 500 mg;

Creatine - 500 mg;

Caffeine citrate - 50 mg;

Citric acid - 3,000 mg;

Sodium bicarbonate - 300 mg;

Sorbitol - 130 mg;

Flavoring agent. The effectiveness of the proposed composition was also tested in a study on the authors themselves in the Ratatype typing test. The essence of the test is typing text on a computer for 1 minute in the browser of the www.ratatype.com website (https://www.ratatype.ua/typing-test/). The typing speed is automatically measured in characters/min - how many characters per minute are typed without errors. Any symbol, including spaces, is considered a "character". Only correctly typed words are taken into account. As a result, the speed (in characters/min) and the accuracy of the typed text (in %) are determined. The authors performed the test typing for 2 days in a row, in the morning and in the evening. Day 1 is a control day, day 2 is an experimental day, when the composition according to the invention was taken in the best version 15 minutes before the test.

Results.

Researcher 1.

Day 1: in the morning - 203 characters/min, accuracy 97%; in the evening - 188 characters/min, accuracy 96%.

Day 2: in the morning - 206 characters/min, accuracy 97%; in the evening - 208 characters/min, accuracy 98%.

Explorer 2.

Day 1: in the morning - 200 characters/min, accuracy 98%; in the evening - 184 characters/min, accuracy 96%.

Day 2: in the morning - 204 characters/min, accuracy 97%; in the evening - 200 characters/min, accuracy 98%.

As can be seen from the obtained results, the test performance in the morning by both researchers gave a better result than in the evening, when fatigue was felt. The use of the composition in the morning of the 2nd day (without fatigue) has little effect on the test results, although there is a certain increase (approximately 2.5%) in both the speed and accuracy of performance for both researchers. However, taking the composition in the evening leads to a significant improvement in the speed (more than 10%) and accuracy (2%) for both researchers, which indicates the normalization of the functions of the nervous system for signal processing (speed) and prompt decision-making (accuracy) during the development of a state of fatigue.

In addition, the eugeroic compound reduced the subjective feeling of evening lethargy and drowsiness after use in each of the researchers. Industrial acceptability. All substances are available on the market. A person skilled in the art will have no difficulty in producing a form of the composition according to the invention using generally accepted methods and means.

Claims

CLAUSE OF INVENTION 1. A composite eugeroic agent based on amino acids, characterized in that it contains amino acids or their derivatives selected from the group: dextrorotatory, levorotatory or racemic tyrosine, dextrorotatory, levorotatory or racemic histidine, dextrorotatory, levorotatory or racemic acetyltyrosine, dextrorotatory, levorotatory or racemic acetylhistidine, 2-methylguanidinoacetic acid (creatine) or its phosphoderivatives in the form of pharmaceutically acceptable salts. 2. A composite eugeroic agent according to paragraph 1, characterized in that for every 1 mass fraction of tyrosine there are from 0.2 to 5 mass fractions of histidine and creatine. 3. A composite eugeroic agent according to paragraph 1 or paragraph 2, characterized in that for every 1 mass fraction of tyrosine there is additionally from 0.2 to 1 mass fraction of a psychostimulant. 4. A composite eugeroic agent according to paragraph 3, characterized in that the psychostimulant is caffeine in the form of a pharmaceutically acceptable salt or its plant equivalent. 5. A composite eugeroic agent according to paragraph 3, characterized in that the psychostimulant is modafinil or its derivative in the form of a pharmaceutically acceptable salt. 6. A composite eugeroic agent according to paragraph 1, characterized in that it is made in the form of a lollipop or an effervescent tablet, or a solution, or a drink.