JP2008088162A - Sleep-aid medicine and sleep-aid supplementary food - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sleep-aid medicine and a sleep-aid supplementary food which are regularly usable with ease and with no possibility of imparting side effects. <P>SOLUTION: The sleep-aid medicine containing, as an effective ingredient, a dipeptide including at least one of histidine and a histidine derivative, and the sleep-aid supplementary food containing the sleep-aid medicine can be used regularly with ease over long periods with no possibility of imparting side effects, and can promote natural continuous sleeping. Further, administration thereof in combination with existent sleeping pills can reduce the use amount of the sleeping pills to reduce possible occurrence of side effects of the sleeping pills. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a sleep aid and a sleep supplement that are effective for sleep disorders such as insomnia by promoting sleep prolongation.

  Many studies on sleep have been reported so far, for internal substances that have the effect of promoting sleep, sleep promoting substances (SPS), delta sleep-inducing peptides, muramyl peptides, uridine and oxidized glutathione, etc. Many researchers have identified as a candidate substance.

Among known substances, many compounds such as prostaglandins (PG) and various peptide hormones are attracting attention as candidate substances. Among them, it is known from research on the molecular mechanism of sleep regulation that PGD ₂ (prostaglandin D ₂ ) is an endogenous sleep promoting substance and PGE ₂ (prostaglandin E ₂ ) is a wakeful substance. .

  As a treatment method for sleep disorders, particularly insomnia, drugs corresponding to the symptoms are generally prescribed while improving lifestyles and the environment, and treating the causative diseases. In addition, a sleep-inducing agent is prescribed for patients who simply have difficulty falling asleep, and a highly stable sleep effect is obtained by balancing the autonomic nerves and relaxing the muscles.

  Currently, the types of hypnotics are classified according to structural characteristics, but some hypnotics may cause unfavorable side effects such as lightheadedness, head feelings, malaise, and emotional instability due to addiction. Taking hypnotics without it is very dangerous. Therefore, there is a demand for a sleep promoting agent that can be safely used on a daily basis without fear of side effects. For example, Patent Document 1 describes a sleep promoting action composition containing theanine, which is a glutamic acid derivative and an amino acid contained in a large amount in tea leaves.

WO 01/74352 pamphlet

  An object of the present invention is to provide a sleep aid and a sleep supplement that can be safely used on a daily basis without fear of side effects.

  In order to solve the above problems, the present inventors focused on dipeptides having an anti-stress action, and as a result of intensive research, dipeptides containing at least one of histidine and histidine derivatives have an effect of promoting sleep extension ( It has been found that it has an SPS-like action) and has led to the present invention.

  That is, the sleep aid according to the present invention includes a dipeptide containing at least one of histidine and a histidine derivative. The “dipeptide containing at least one of histidine and a histidine derivative” also includes “a dipeptide composed of only histidine” and “a dipeptide composed of one or two histidine derivatives”. A histidine derivative refers to a substance in which part of hydrogen of histidine is substituted with a functional group such as an alkyl group (such as a methyl group, an ethyl group, or a propyl group), a benzyl group, or an acetyl group.

  In this specification, "promoting sleep extension" means maintaining the homeostasis of living body related to sleep and promoting the progression of natural sleep, and the sleep aid has a sleep extension promoting action. Say. In the present invention, it is unclear as to what mechanism the dipeptide containing at least one of histidine and a histidine derivative exhibits a sleep extension promoting action, but histidine or a histidine derivative is related to sleep and has some effect on it. It is presumed that the above action is expressed.

  In the sleep aid according to the present invention, as a dipeptide containing at least one of histidine and a histidine derivative, carnosine (also known as β-alanyl-histidine), carnosin β-alanine is substituted with γ-aminobutyric acid, Carnosine (Homocarnosine, also known as γ-aminobutyric acid-histidine), anserine (Anserine, also known as β-alanyl-methylhistidine) having a carnosine-like structure is desirable.

  Carnosine, homocarnosine, and anserine are substances that are abundant in animal brain, heart, stomach, and especially skeletal muscles. They already have an anti-fatigue effect (adjusting the pH value of muscles to regulate energy metabolism and functions of body tissues). Improved), antioxidant effect (removes active oxygen, which causes various lifestyle-related diseases), tissue repair promotion effect (activates the fibroblast tissue of the skin, promotes the rate of collagen synthesis), etc. It is known to have and is used as a raw material for many supplements. Therefore, taking or ingesting these as sleep aids is very effective in that they can be used daily as a supplement without any fear of side effects.

  Carnosine, homocarnosine and anserine are preferably derived from natural products. If these are derived from natural products, they can be used with confidence because they are only in the L form, as well as carnosine, homocarnosine and anserine contained in the human body.

  Moreover, since the sleep supplement containing the sleep aid can be consumed as a normal meal or supplement, it is desirable when continuous intake of the sleep aid is necessary.

  The sleep aid of the present invention has no fear of side effects and can be used on a daily basis for a long period of time without anxiety. In addition, by taking in combination with existing sleeping pills, the amount of sleeping pills used can be reduced and the risk of side effects of sleeping pills can be reduced.

  The dipeptide containing at least one of histidine and a histidine derivative used in the embodiment of the present invention may be either a synthetic product or a natural product. Moreover, the form of a salt may be sufficient. These dipeptides exist in D-form, L-form, and DL-form, and any of them may be used. However, since dipeptides containing at least one of histidine and histidine derivatives existing in the living body are mostly in L-form, Are preferably used.

  Carnosine, homocarnosine, and anserine, which are dipeptides containing at least one of histidine and histidine derivatives, are D-form, L-form, and DL-form and have an action to promote sleep elongation, but carnosine, homocarnosine, and anserine derived from natural products are all L Since it is a body, when using it as a functional food and drink as a sleep supplement and a supplement, it is desirable that it is L body. Hereinafter, L-form carnosine, homocarnosine, and anserine are referred to as L-carnosine, L-homocarnosine, and L-anserine.

  Hereinafter, although embodiment in the case of L-carnosine, L-homocarnosine, and L-anserine is shown, this invention is not limited to these.

  The natural product containing L-carnosine, L-homocarnosine, and L-anserine is not particularly limited as long as it contains these dipeptides as a natural product. In addition, boiled juice that is discarded during the production of canned tuna, salmon and the like, or those extracted from inexpensive raw materials such as waste chicken can be used. As a sleep aid or sleep supplement containing L-carnosine, L-homocarnosine, and L-anserine as an active ingredient, natural products containing L-carnosine, L-homocarnosine, and L-anserine can be directly used or extracted. Or purified high-purity products (including high-purity synthetic products) that have been separated and purified from the above.

  Extraction and purification from L-carnosine, L-homocarnosine, and L-anserine-containing materials in the present embodiment is, for example, cold water extraction, hot water extraction, filtration using raw materials such as the above-mentioned broth and waste chicken as starting materials -Solid separation by centrifugation, solid-liquid separation by centrifugation, desalting by reverse osmosis membrane, desalting by electrodialysis, fractionation by ultrafiltration membrane, adsorption elution fractionation by porous resin, fractionation by molecular sieve chromatography, ion This refers to an extraction purification method such as fractionation by exchange resin chromatography, concentration under reduced pressure, concentration at normal pressure, concentration crystallization, vacuum drying, hot air drying or freeze drying, and these can be used alone or in combination. The content of the purified L-carnosine, L-homocarnosine, and L-anserine can be selected in consideration of restrictions on the production of food and drink to be taken and physical properties of the product.

  In the present embodiment, L-carnosine, L-homocarnosine, and L-anserine may be in the form of a salt, and a salt based on a carboxylic acid group and an amino group contained in the molecule alone or both is possible. Examples of the salt based on the carboxylic acid group include metal salts such as sodium, potassium, calcium, magnesium, iron, zinc, copper and selenium, and ammonium salts. Examples of salts based on amino groups include inorganic salts and organic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, succinic acid and maleic acid. These salts can be produced by a known method by reacting free L-carnosine, L-homocarnosine and L-anserine with a selected acid or base. These can be used alone or in combination.

  The form of the sleep aid of this embodiment is not particularly limited, and any dosage form may be used as long as it is used for normal oral administration or parenteral administration. For example, powders, granules, tablets, capsules, enteric solvents, troches, liquids for internal use, liquids for external use, suspensions, emulsions, syrups, injections, infusions, nasal drops, eye drops, ear drops, seats An agent, a shipping agent, an inhalant or an ointment can be arbitrarily selected depending on the purpose of use. In the preparation, adjuvants such as excipients, binders, disintegrants, lubricants, flavoring agents, stabilizers and the like may be used as the main agent depending on the purpose.

  The manufacturing method of the sleep aid of this embodiment varies depending on the purpose and dosage form, but can be manufactured and processed by conventional methods conventionally used in various fields.

  The dosage of the sleep aid of the present embodiment varies depending on age, body weight, symptoms, administration route, dosage form, etc., but usually for adults, the amount of L-carnosine is usually 100 mg to 6 g per day, preferably per day. 300 mg to 1.2 g is preferred. The amount of L-homocarnosine is preferably 100 mg to 6 g per day, preferably 450 mg to 600 mg per day. The amount of L-anserine is 100 mg to 6 g per day, preferably 300 mg to 600 mg per day.

  Moreover, the sleep supplement of this Embodiment may mix | blend protein, saccharides, fat, a trace element, vitamins, an emulsifier, and a fragrance | flavor with L-carnosine, L-homocarnosine, and L-anserine. In functional food and drink, it can also be set as processing forms, such as a natural liquid food, a semi-digested nutrient food, a component nutrient food, and a drink. In addition, solid or liquid foods or luxury products such as bread, noodles, rice, confectionery (biscuits, cookies, cakes, candy, chocolate, chewing gum, Japanese confectionery, etc.), foods such as tofu and processed products thereof, sake , Fermented foods such as medicinal liquor, mirin, vinegar, soy sauce, miso, livestock farming foods such as dressing, yogurt, ham, bacon, sausage, mayonnaise, fishery products such as kamaboko, fried tempura, humpen, fruit juice beverage, soft drink, It can also serve as beverages such as sports drinks, alcoholic drinks and tea. In addition, it is possible to make the user widely recognize the function of food and drink by attaching a label indicating that the sleep supplement is treated / prevented for insomnia or sleep is improved on the package or container of the sleep supplement. it can.

  Hereinafter, preferred embodiments of the present invention will be described in more detail using examples. The objects, features, advantages and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and it is easy for those skilled in the art to reproduce the present invention based on the description of the present specification. The specific examples described below are provided as illustrations or illustrations of preferred embodiments of the invention and the invention is not limited thereto. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.

(Example 1) Pentobarbital sleep prolongation effect by oral administration of L-carnosine, L-homocarnosine, and L-anserine L-carnosine, L-homocarnosine, and L-anserine were dissolved in physiological saline. L-carnosine, L-homocarnosine, and L-anserine were administered orally (po) at a dose of 10 mg / kg in 10 mice per group, and pentobarbital was intraperitoneally administered at a dose of 40 mg / kg 15 minutes later. (I.p.) Sleep time was measured using the time from administration and disappearance of the right-angle reflex to normality as a sleep index. The control group was administered with physiological saline and compared with L-carnosine and the like.

  The results are shown in FIG. In addition, p in the figure means probability (probability), for example, p <0.05 represents “significant difference at 5% risk”. As shown in FIG. 1, all showed a significant pentobarbital sleep prolonging action as compared to the control group. The pentobarbital sleep prolonging action of L-carnosine, L-homocarnosine, and L-anserine was significantly prolonged by about 3 times, about 3 times, and about 3.5 times, respectively, as compared with the control group. Of the three dipeptides, L-anserine was the strongest, followed by L-anserine> L-carnosine> L-homocarnosine. Therefore, these dipeptides are absorbed from the small intestine and show that they are acting.

(Example 2) Pentobarbital sleep prolongation effect in intraperitoneal administration of L-carnosine, L-homocarnosine, and L-anserine 2-1: Dose dependency in pentobarbital sleep prolongation effect of L-carnosine The same as in Example 1 The pentobarbital sleep prolongation action was examined by the method. L-carnosine was administered intraperitoneally (ip) to each mouse at doses of 5, 10 and 20 mg / kg, and pentobarbital sleep prolongation action was compared with the control group 15 minutes later. As a result, as shown in FIG. 2, the 5,10 and 20 mg / kg intraperitoneal (ip) pre-administration groups of L-carnosine showed significant pentobarbital sleep prolongation in a dose-dependent manner compared to the control group. The effect was shown. Therefore, it is clear that the prolongation of pentobarbital sleep by L-carnosine administration is an effect by L-carnosine administration.

2-2: Dose Dependence in Pentobarbital Sleep Prolonging Action of L-Homocarnosine Pentobarbital sleep prolonging action was examined in the same manner as in Example 1. L-homocarnosine was administered intraperitoneally (ip) to each mouse at doses of 5,7.5 and 10 mg / kg, and the pentobarbital sleep prolongation effect 15 minutes later was compared with the control group. As a result, as shown in FIG. 3, the pre-administration groups of L-homocarnosine 5,7.5 and 10 mg / kg intraperitoneal (ip) were significantly pentose dose-dependently compared to the control group. It showed a prolonged action of barbital sleep. Therefore, it is clear that the extension of pentobarbital sleep by L-homocarnosine administration is the effect of L-homocarnosine administration, as with L-carnosine.

2-3: Dose Dependence in Pentobarbital Sleep Prolonging Action of L-Anserine Pentobarbital sleep prolonging action was examined in the same manner as in Example 1. L-Anserine was administered intraperitoneally (ip) to each mouse at doses of 5,7.5 and 10 mg / kg, and 15 minutes later, the pentobarbital sleep prolongation action was compared with the control group. As a result, as shown in FIG. 4, 5,7.5 and 10 mg / kg intraperitoneal (ip) pre-administration groups of L-anserine showed significant pentobarbital in a dose-dependent manner compared to the control group. It exhibited sleep prolongation. Therefore, it is clear that the extension of pentobarbital sleep by L-anserine administration is an effect by L-anserine administration, like L-carnosine and L-homocarnosine.

  As a result, it was found that the dipeptide administration group showed a significant pentobarbital sleep prolongation action as compared with the control group. When compared at the dose of 10 mg / kg, the L-homocarnosine administration group was the strongest at about 3 times for the three dipeptides, and the pentobarbital sleep prolongation effect of the L-carnosine and L-anserine administration group was about 2 times. It was comparable.

(Example 3) Pentobarbital sleep prolongation effect in intracerebroventricular administration of L-carnosine, L-homocarnosine and L-anserine L-carnosine, L-homocarnosine and L-anserine were dissolved in physiological saline. L-carnosine, L-homocarnosine, and L-anserine were pre-administered intraventricularly (icv) at a dose of 10 mg / kg in 10 mice per group, and pentobarbital sleep prolongation action was controlled 15 minutes later in the control group And compared. As a result, as shown in FIG. 5, only the L-anserine administration group showed a significant pentobarbital sleep prolongation action as compared to the control group, but other L-carnosine and L-homocarnosine were effective in prolonging sleep. Although there was a tendency, no significance was observed.

(Example 4) Pentobarbital sleep prolongation action in intraperitoneal pre-administration of a dipeptide containing at least one of histidine and histidine derivatives other than L-carnosine, L-homocarnosine, and L-anserine

  In Example 4, the amino acids constituting the dipeptide used are described in the following abbreviations in parentheses.

  That is, L-histidine (His), L-glycine (Gly), L-valine (Val), L-isoleucine (Ile), L-leucine (Leu), L-serine (Ser), L-methionine (Met) L-phenylalanine (Phe), L-tyrosine (Tyr), L-aspartic acid (Asp), L-arginine (Arg), L-alanine (Ala), L-proline (Pro), L-glutamic acid (Glu) L-lysine (Lys), L-glutamine (Gln), L-asparagine (Asp), L-cysteine (Cys), L-tryptophan (Trp), and L-threonine (Thr).

  In addition, as a notation of a dipeptide, an abbreviation of an amino acid having an N-terminus from which an α-amino group is released is conventionally shown on the left side, and an abbreviation of an amino acid having a C-terminus from which an α-carboxyl group is released on the right side. Although the method is taken, this notation is also used in this specification. That is, for example, in a dipeptide composed of L-histidine and L-glycine, when L-histidine has an N-terminus and L-glycine has a C-terminus, it is expressed as His-Gly.

  Dipeptides are dissolved in physiological saline and administered orally (po) at a dose of 10 mg / kg to 10 mice per group, and 15 minutes later, pentobarbital is administered intraperitoneally at a dose of 40 mg / kg (i. p.) was administered, and the sleep time was measured using the time from the disappearance of the direct reflex to the return to normal as an indicator of sleep. The control group was administered with physiological saline and compared with L-carnosine and the like.

  FIG. 6 shows the test results showing the pentobarbital sleep prolongation effect in preperitoneal administration of Gly-His, Val-His, Ile-His and Leu-His. In the Gly-His, Val-His, Ile-His and Leu-His administration groups, a significant pentobarbital sleep prolongation effect was observed only in the Val-His administration group compared to the control group. In addition, the action of the Val-His administration group was weaker than that of the L-carnosine, L-anserine and L-homocarnosine administration groups.

  FIG. 7 shows the test results showing pentobarbital sleep prolongation effect in intraperitoneal pre-administration of Ser-His, Met-His, Phe-His, Tyr-His, Asp-His and Arg-His. Ser-His, Met-His, Phe-His, Tyr-His, Asp-His, and Arg-His administration groups showed a tendency to prolong pentobarbital sleep compared to the control group, especially in the Phe-His administration group. Showed a significant pentobarbital sleep prolongation effect.

  FIG. 8 shows pentobarbital in intraperitoneal pre-administration of His-Gly, His-Ala, His-Leu, His-Ser, His-Tyr, His-Pro, His-Asp, His-Glu, His-Lys and His-Arg. The test result which shows sleep prolongation effect is shown. His-Gly, His-Leu, His-Ser, His-Tyr, His-Pro, His-Asp, His-Glu, structural isomers of these dipeptides, including L-carnosine, L-anserine and L-homocarnosine The His-Lys and His-Arg administration groups did not show significant pentobarbital sleep prolongation compared to the control group. However, it was revealed that the His-Ala administration group showed a significant pentobarbital sleep prolongation effect comparable to that of the L-carnosine administration group.

The test result which shows the pentobarbital sleep prolongation effect in the intraperitoneal pre-administration of His-Trp in FIG. 9 is shown. The His-Trp administration group showed significant pentobarbital sleep prolongation comparable to the L-carnosine and His-Ala administration groups.
Furthermore, the test result which shows the pentobarbital sleep prolongation effect in the intraperitoneal pre-administration of His-His in FIG. 10 is shown. The His-His administration group had a significant pentobarbital sleep prolongation action, similar to L-carnosine. Therefore, it was found that His-containing dipeptides have an action of prolonging pentobarbital sleep.

  The present invention is useful as a sleep aid and a sleep supplement that can be used on a daily basis for a long time without fear of side effects, can be used for a long period of time, can easily fall asleep and prolong sleep. It can be suitably used as a therapeutic method useful for a patient suffering from insomnia or a preventive method thereof.

It is a test result which shows pentobarbital sleep prolongation effect in the oral administration of L-carnosine, L-homocarnosine, and L-anserine. It is a test result which shows the dose dependence of the pentobarbital sleep prolongation effect in the intraperitoneal administration of L-carnosine. It is a test result which shows the dose dependence of the pentobarbital sleep prolongation effect in the intraperitoneal administration of L-homocarnosine. It is a test result which shows the dose dependence of the pentobarbital sleep prolongation effect in the intraperitoneal administration of L-anserine. It is a test result which shows the pentobarbital sleep prolongation effect in the intraventricular administration of L-carnosine, L-homocarnosine, and L-anserine. It is a test result which shows pentobarbital sleep prolongation effect in the intraperitoneal pre-administration of Gly-His, Val-His, Ile-His, and Leu-His. It is a test result which shows the pentobarbital sleep prolongation effect in the intraperitoneal pre-administration of Ser-His, Met-His, Phe-His, Tyr-His, Asp-His, and Arg-His. Pentobarbital sleep prolongation effect in intraperitoneal pre-administration of His-Gly, His-Ala, His-Leu, His-Ser, His-Tyr, His-Pro, His-Asp, His-Glu, His-Lys and His-Arg It is a test result which shows. It is a test result which shows the pentobarbital sleep prolongation effect in intraperitoneal pre-administration of His-Trp. It is a test result which shows pentobarbital sleep prolongation effect in intraperitoneal pre-administration of His-His.

Claims (4)

  A sleep aid comprising as an active ingredient a dipeptide containing at least one of histidine and a histidine derivative.   The sleep aid according to claim 1, wherein the dipeptide is at least one dipeptide selected from the group consisting of carnosine, homocarnosine, and anserine.   The sleep aid according to claim 2, wherein the dipeptide is derived from a natural product.   A sleep supplement containing the sleep aid according to any one of claims 1 to 3.

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