JP2019119699A - Composition for improving mental state - Google Patents

Abstract

To provide oral compositions containing lactoferrin.SOLUTION: Provided is an oral composition for improving sleep onset, sleep continuity, and mood after wake up (reduction of negative mental status, such as fatigue and anxiety/embarrassment), by taking liposome encapsulating lactoferrin, having the effect of improving mental status to a more active state in the time of activity after wake up. More than half of the lactoferrin contained in the composition is present in the state of being encapsulated in the liposome.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a composition for improving sleep which qualitatively improves sleep state and improves mental state to a more active state during wake-up activity. Specifically, I improved the sleeping condition, the sleep continuity, the feeling at the time of waking up (reduction of negative mental state such as fatigue, anxiety, embarrassment etc.), and I got tired from the activity after waking up. For improving mental status, which can improve mental status to a more active state by giving awareness such as "active", "head was clear" and "concentration was improved" It relates to a composition.

  Sleep is known to be deeply related to the physical and mental state when awakening and working, and in people who live in social life in recent years with many opportunities to receive various strong stress, sleep such as sleep disorder As a result, the quality of life is deteriorating, and the number of people who feel pain is increasing year by year. In recent years, as more people recognize that there is a relationship between the state of sleep and the mental state of daytime activities, the need to secure high-quality sleep has emerged and is increasing. On the other hand, as a means to improve sleep, if you have a pathological level, you can consult with a medical institution, and you can receive the use of medicines such as sleep inducers or counseling etc. There is a problem that simple and effective measures can not be secured for people who feel that they often feel ill, such as feeling ill.

  For this reason, various methods for improving sleep have been proposed. For example, a method of using a system that advises a method of qualitatively improving sleep by collecting sleep information, lifestyle information and life situation information using sensors etc. (Patent Document 1), bedding Method to improve by adding the function of temperature control (Patent Document 2), Method to improve by stimulating sense of smell using aroma components (Patent Documents 3 and 4), Oral intake of ingredients contained in animals and plants Methods (patent documents 5-7) etc. which are improved. However, these methods are not only insufficient for achieving sufficient effects or difficult to carry out on a continuous basis, but also cause health problems due to continuous intake of a concentration higher than that usually taken for substances not derived from human body There were problems such as the possibility of causing

JP, 2016-122347, A JP, 2015-167639, A JP, 2014-196250, A Unexamined-Japanese-Patent No. 2015-081227 JP, 2016-153387, A JP, 2015-199686, A JP, 2016-079096, A

  The present invention provides an oral composition having the effect of qualitatively improving sleep state and improving mental state during wake-up activity to a more active state, specifically, sleepiness, sleep continuity, Waking up I improved my mood after waking up (reduction of negative mental state such as fatigue, anxiety and embarrassment), and I got tired, active, and head at the time of activity after getting up. It is an object of the present invention to provide an oral composition having an effect of improving the mental state to a more active state by giving awareness such as “concentrated” and “intensified ability”.

  The present inventors improve lactation status and sleep continuity by continuously taking lactoferrin orally, and the mood at the time of getting up is a negative mentality such as "feeling of fatigue" or "feeling of anxiety or embarrassment". It was found that improvement can be achieved by reducing the condition. Furthermore, when lactoferrin, which is continuously taken orally, is replaced with liposomalized “lactoferrin-containing liposome”, “wealed”, “active”, “the head became clear” at the time of activity after getting up. It has been found that the mental state can be improved to a more active state by bringing about awareness such as “being improved in concentration” and the like, and the present invention has been completed.

The present invention includes, for example, the subject matter described in the following sections.
Item 1.
An oral composition for improving mental condition, which comprises lactoferrin and exists in a state in which at least a part of the lactoferrin is encapsulated in a liposome.
Item 2.
Item 3. The oral composition for improving mental condition according to Item 1, which is present in a state in which a major amount or more of lactoferrin contained in the composition is contained in a liposome.
Item 3.
The oral composition for mental state improvement of any one of claim | item 1 or 2 which contains the liposome which encloses lactoferrin as an active ingredient.
Item 4.
The oral composition for improving mental condition according to any one of Items 1 to 3, which is a pharmaceutical composition or a food composition.

  According to the present invention, it is possible not only to improve or eliminate negative mental states such as "fatigue" and "anxiety and embarrassment", as well as to improve sleepiness, sleep continuity, and wake up feeling. The mental state of the day was brought about by bringing awareness such as “I'm tired”, “I was active”, “I was clear” and “I was improving concentration” at the time of later activities. By improving to a more active state, QOL can be improved.

The graph which showed the analysis result in the drinking period of the item which "we got tired" in the questionnaire at bedtime. The graph which showed the analysis result in the drinking period of the "active" item in the questionnaire at bedtime. The graph which showed the analysis result in the drinking period of the item "head was clear" in the questionnaire at bedtime. The graph which showed the analysis result in the drinking period of the "there was concentration" item in the questionnaire at bedtime.

  Lactoferrin is an iron-binding glycoprotein with a molecular weight of about 80,000 and is present in mammalian milk, saliva, tears, semen, various mucuses, and the like. Also in human milk, it is abundantly present in breast milk, especially in colostrum which is abundantly secreted in a few days after delivery, and it is thought that it plays an important role in maintaining health such as neonatal immunity acquisition. In addition, lactoferrin is widely distributed in newborns and in the body. For example, it is contained in secretions such as saliva, tears, duodenum, etc., and is considered to play an important role for other than neonates. Although lactoferrin used in the present invention is preferably extracted from milk in terms of cost, the origin is not particularly limited. In addition, it may be apolactoferrin, natural lactoferrin or holo lactoferrin. Specifically, ion exchange from mammalian (eg, human, cow, buffalo, horse, goat, sheep, etc.) colostrum, transitional milk, ordinary milk, end-stage milk, etc. Lactoferrin separated by a conventional method such as chromatography, apolactoferrin obtained by removing iron from lactoferrin by a conventional method, metal-bound lactoferrin obtained by partially chelating metal such as iron, copper, zinc or manganese to apolactoferrin, or the metal Fully chelated metal-saturated lactoferrin, etc. can be used. In particular, lactoferrin derived from bovine or human is preferred. As a commercial item, Morinaga lactoferrin MLF-EX (made by Morinaga Milk Industry Co., Ltd.), "Bioferrin" (made by Glanbia Nutritionals), "Lactoferrin" (made by Fonterra) can be used preferably, for example.

  The lactoferrin used in the present invention needs to be at least partially encapsulated in a liposome. In particular, it is more preferable to increase the content of lactoferrin contained in the liposome in the composition, and it is further preferable that a major amount of lactoferrin contained in the composition is contained in the liposome, and contained in the composition. It is most preferable that almost all the lactoferrin to be contained is contained in the liposome. In addition, the present invention also discloses an oral composition for improving mental condition, which contains "a liposome containing a lactoferrin" as an active ingredient. The term "included" as used in the present invention means a state included in the structure of lipid vesicles (liposomes) formed mainly of a lipid bilayer membrane. It is preferable that the liposome is enclosed in a space surrounded by a liposome membrane which is a lipid bilayer membrane, but it may be present together with components of the liposome membrane, and may be present between multiple membranes constituting a multilamellar liposome. It may be present, or may be present in a form attached to or bound to the surface of the outermost membrane of the lipid bilayer membranes constituting the liposome, and is present in all or part of them. Also good. In the present application, “lactoferrin contained in liposome” may be expressed as “liposomalized lactoferrin”, “lactoferrin-containing liposome”, “lactoferrin-containing liposome”, or simply “liposomalized lactoferrin”.

  Liposomes are lipid vesicles and are formed by hydration of phospholipid-based lipids with a sufficient amount of water. Generally, they are classified based on the number of lipid bilayers and classified into multilamellar liposomes (MLV) and unilamellar liposomes. Monolamellar liposomes are further classified into SUV (small unilamella vesicle), LUV (large unilamella vesicle), GUV (giant unilamella vesicle) and the like according to their size. The liposome of the present invention may be any of these. Preferred is MLV. In the present invention, the size of the liposome is usually 30 to 1000 nm, preferably 30 to 600 nm, more preferably 50 to 200 nm.

  As the phospholipid, lecithin or a lecithin derivative is preferable. The lecithin is not particularly limited, and, for example, soybean lecithin, corn lecithin, cottonseed oil lecithin, egg yolk lecithin, egg white lecithin and the like can be used. Also, instead of or in addition to lecithin, a lecithin derivative may be used. As a lecithin derivative, hydrogenated lecithin and those obtained by introducing polyethylene glycol, aminoglycans to phospholipids in lecithin exemplified above can be exemplified. Among these, soybean lecithin, egg yolk lecithin and hydrogenated egg yolk lecithin are preferable, and soya lecithin and egg yolk lecithin are more preferable. In addition, it is also possible to use purified lecithin in which the purity of phospholipid (for example, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl glycerol, sphingomyelin, etc.) is increased. These lecithin and lecithin derivatives may be used singly or in combination of two or more.

  Liposomes containing lactoferrin (lactoferrin-containing liposomes) can be produced by conventional methods. For example, after solubilizing the desired amount of lecithin and optionally the desired amount of sterol with a suitable organic solvent such as, for example, ethanol, removing the solvent under reduced pressure, preparing membrane lipid, lactoferrin or any other An aqueous solution containing a physiologically active substance is added, and stirred, for example, at about 1000 to 3000 rpm for about 2 to 5 minutes to prepare a liposome suspension, whereby a liposome in which lactoferrin is encapsulated can be obtained.

  Also, separately from this method, the desired amount of lecithin and optionally the desired amount of sterol are dissolved in a small amount of ethanol, dispersed in an aqueous solution or buffer and preemulsified, and then dispersed under high pressure to By forming an overlay and preparing a liposome suspension, it is also possible to obtain a liposome in which lactoferrin is encapsulated.

The preparation method of the liposome dispersion is not limited to the above-mentioned method, and can be prepared by a known method. For example, the following methods (1) to (4) may be mentioned.
(1) A method of forming a liposome by mixing phospholipids (lecithin), lactoferrin and other components, and then hydrating with an aqueous solution containing a pH adjusting agent, polyhydric alcohol, saccharides and the like,
(2) A method of dissolving phospholipids (lecithin), lactoferrin and other components in alcohol or polyhydric alcohol and hydrating with an aqueous solution containing pH adjusting agent, polyhydric alcohol, saccharides and the like to form liposome,
(3) A method of forming a liposome by complexing phospholipid (lecithin), lactoferrin and other components in water using an ultrasonic wave, a French press, a homogenizer or the like.
(4) A method of mixing and dissolving phospholipid (lecithin), lactoferrin and other components in ethanol, adding the ethanol solution to an aqueous potassium chloride solution and then removing ethanol to form a liposome.

  The liposome of the present invention preferably contains a sterol. Sterols include animal-derived sterols such as cholesterol, lanosterol, dihydrolanosterol, desmosterol and dihydrocholesterol; Sterols (phytosterols) derived from microorganisms; sterols derived from microorganisms such as timosterol, ergosterol and the like, and the like, and can be used singly or in combination of two or more. Among these, cholesterol or phytosterol is preferably used.

  The molar ratio of lecithin to sterol in the liposome is preferably about 55:45 to 95: 5, more preferably about 60:40 to 90:10, and most preferably about 75:25 to 85:15. When the molar ratio is in these ranges, the stability of the liposome membrane is improved. The content of lecithin or sterol can be measured by a known method. For example, the content of lecithin can be quantified by, for example, the Fiske-Subbarow method, and the content of sterols by HPLC, a colorimetric method, or the like.

  The obtained suspension of liposomal lactoferrin may be subjected to an operation of removing lactoferrin in the liposome outer solution, for example, an operation of filtering the suspension and dialyzing the obtained filtrate, if necessary. Moreover, although the suspension of a liposome can be used also as a liquid, it can also be used as a lyophilised dried material. Liposomes can be in a form suitable for various oral intakes, including tablets and encapsulated dried products thereof.

  The contents of lactoferrin, lecithin and sterol in the suspension of liposomal lactoferrin are as follows. The content of lactoferrin is preferably about 10 to 99% by mass, more preferably about 20 to 95% by mass, and still more preferably about 30 to 90% by mass. The content of lecithin is preferably about 1 to 80% by mass, more preferably about 3 to 65% by mass, and still more preferably about 5 to 50% by mass. The sterol content is preferably about 0 to 40% by mass, more preferably about 0.1 to 30% by mass, and still more preferably about 1 to 20% by mass. If the content of lactoferrin is up to about twice the content of lecithin, it is possible to encapsulate almost all of lactoferrin in the liposome.

  Furthermore, the surface of the lactoferrin-containing liposome can be coated, and this coating can also be used as an active ingredient. Preferred coatings include coatings with polysaccharides containing sulfate groups. The sulfate group-containing polysaccharides include fucoidan, carrageenan, agar, heparin and the like. Further, the sulfate group-containing polysaccharide also includes a sulfated polysaccharide which is sulfated, and may be, for example, chondroitin sulfate, dermatan sulfate or the like.

  As the sulfate group-containing polysaccharide, one having a molecular weight of about 5,000 to 300,000 is preferably used. Among these sulfate group-containing polysaccharides, fucoidan and carrageenan can be preferably used, and fucoidan is particularly preferable. The amount of the sulfate group-containing polysaccharide used is, for example, preferably about 10 to 500 parts by mass, and more preferably about 20 to 200 parts by mass with respect to 100 parts by mass of lecithin contained in the liposome.

  The coating can be performed, for example, by adding a sulfate group-containing polysaccharide to a suspension containing liposomal lactoferrin and stirring at about 1000 to 3000 rpm for about 2 to 5 minutes. In addition, a plurality of liposomes may be contained in one coating membrane. The fact that the liposome is coated with the sulfate group-containing polysaccharide can be confirmed, for example, by changing the zeta potential of the liposome solution when the sulfate group-containing polysaccharide is added and stirred.

  The oral composition for mental condition improvement containing the lactoferrin-encapsulating liposome according to the present invention realizes "high-quality sleep" in which sufficient sleep and sleep can be obtained, and it is difficult to feel sleepiness when waking up, and fatigue recovery In addition to being less likely to feel a positive feeling or to have negative thinking tendencies, it brings awareness such as “I'm tired”, “I was active”, “I was clear”, “I was improving my concentration”, etc. By this, it is possible to obtain an improvement effect of more active mental state during daytime activities.

  The content of lactoferrin (lactoferrin alone) in the oral composition for improving mental condition of the present invention is not particularly limited as long as the effects of the present invention are exhibited. For example, about 1 to 10000 mg, 5 to 5000 mg, 10 to 2000 mg, or about 20 to 1000 mg can be exemplified. Also, the content ratio is not particularly limited, and can be, for example, about 0.1 to 100% by mass, 1 to 99% by mass, or about 10 to 80% by mass. The intake of lactoferrin when the oral composition for improving the mental condition is ingested is not particularly limited, but it may be, for example, 10 to 10000 mg per day for adults from the relationship between the intake and the effects obtained. -5000 mg is preferable, 30-500 mg is more preferable, 50-300 mg is more preferable, 100-200 mg is the most preferable.

  Moreover, it is preferable to ingest an oral composition for mental condition improvement containing a lactoferrin-encapsulating liposome once or several times (preferably 2 to 3 times) per adult. In the case of a child, it is preferable to limit the number of intakes or to limit the intake per dose depending on the age. As a method of restriction, for example, a method of reducing the number of portions to be taken in a plurality of ingested portions for adults, providing a dividing line in a tablet or punch and dividing according to the intake amount, and the like can be mentioned. Although the subject to which the intake is applied is preferably human, it may be a non-human non-human mammal. Also when the application target is a non-human mammal (for example, a pet or a domestic animal, more specifically, a dog, a cat, a monkey, a cow, a pig, a sheep, etc.), appropriately set the administration or intake of the human concerned as a reference. Can.

  The oral composition for improving mental condition of the present invention is a pharmaceutical composition, a quasi-drug composition or a food composition (food for patients, food for specified health use, food for functional indication, nutritional supplement, health food, It can be preferably used as functional food.

  When used as pharmaceutical compositions or quasi-drugs, other ingredients include pharmaceutically acceptable carriers, carriers, and / or additives (eg, solvents, dispersants, emulsifiers, buffers, stabilizers, Excipients, binders, disintegrants, lubricants and the like can be exemplified. In addition, the form of the pharmaceutical composition is also not particularly limited, and tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules and the like can be exemplified. These forms of the pharmaceutical preparation can be prepared by combining the other components and liposomal lactoferrin, if necessary, by a conventional method.

  When used as a food composition, examples of other ingredients include food hygiene acceptable bases, carriers, additives, and other ingredients / materials that can be used as food. In addition, the form of the food composition is also not particularly limited, and, for example, health food for health, food for nutrition, food for functional health, food for health such as food for functional indication; food for sick, milk powder for pregnant lactating women, infant formula So-called health foods such as special purpose foods such as nutritional supplements, health supplements, nutritionally adjusted foods, supplements, etc. Prepared foods for sick people (hospital food, sick food or care food etc.) and the like. These can be prepared by conventional methods. In particular, food for health use such as food for specified health use, food for nutrition function, food for functional indication; food for sick people, milk powder for pregnant and lactating women, special use food such as infant formula, milk supplements, health supplements, When preparing a food composition as a so-called health food such as a nutraceutical food, supplement, etc., for example, granules, capsules, tablets (including chewable agents), beverages (beverage powder) so as to facilitate continuous intake Are preferably prepared in the form of, for example, a drink, etc., among which the form of capsules, tablets, tablets, beverage powders, drinks is preferred in view of the ease of intake, but it is particularly limited thereto. Absent. Among the food compositions, when used as a food additive composition, examples of the form thereof include liquid, powder, flakes, granules, and paste.

  There are no particular limitations, but as components other than the above that can be incorporated into the oral composition for improving mental condition of the present invention, dextrin, cellulose, lecithin (in particular from soybean), fine particle silicon dioxide, calcium stearate etc. Preferably illustrated.

  In the present specification, the term "comprising" also includes "consisting essentially of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of.").

Hereinafter, the present invention will be specifically described, but the present invention is not limited to the following examples.
Morinaga Lactoferrin MLF-EX (manufactured by Morinaga Milk Industry Co., Ltd.) was used as a test composition for examining the influence of lactoferrin on sleep state . MLF-EX is a food material containing 90% or more of bovine-derived LF which is an existing natural food additive. In addition to MLF-EX, dextrin, cellulose, lecithin (derived from soybean), finely divided silicon dioxide and calcium stearate were blended and compressed into tablets (300 mg). At the time of production, the raw material amount was adjusted to contain 270 mg of LF per 6 tablets (that is, containing 45 mg of lactoferrin per 300 mg of one tablet). Also, tablets in which MLF-EX was replaced with dextrin as a placebo were similarly produced. The subjects took six tablets of these tablets daily for four weeks. When waking up in the morning for all 3 days from the start of the test to 3 days immediately before the start of the test, 3 days immediately after the start of the test and 3 days immediately after the start of the test and 3 days immediately after the start of the test We conducted a questionnaire survey using the OSA sleep survey form MA (OSA sleep inventory MA version) (the Japan Sleep Improvement Council open version). OSA sleep questionnaire MA version: Factor 1: Sleepiness on rising, Factor 2: Initiation and maintenance of sleep, Factor 3: Frequent dreaming, Factor 4 : Refreshing, 5th factor: 5 factor type 16 items question of sleep length (4 steps evaluation. Negative evaluation is from “1” to positive evaluation is “4”. For example, in the first question, , "1" is very tired, "2" is slightly tired, "3" is slightly tired, "4" is very tired. Conducted for the purpose of investigating the psychology and physical condition in each factor from the answer results of 16 questions. In addition, the Japanese version of POMS abbreviated version-for adults (Profile of Mood States-Brief Form Japanese Version) (Three days on the day of the start of the test, and on the day of the second week and the fourth week after the start of the test) Questionnaire survey using Kaneko Shobo) was conducted to evaluate the condition check such as mood and fatigue level. The Japanese version of POMS short version had 35 questions (5 grades. For example, in the first question "People are fun", there was no "0" at all. "1" was a little "2" so there was It consisted of "3", "4", and "7", and it was composed of 7 scales such as (confusion-embarrassment) (tension-anxiety) and negative mood condition comprehensively using a dedicated tool. It is known that the (TMD score) is expressed, and the higher the value, the more negative these scales and scores are. The obtained results are shown in Table 1. The fluctuation value means a numerical value obtained by subtracting the evaluation point at the start of the test from each evaluation point after the start of the test. Also, TMD score (Total Mood Disturbance) is a score that comprehensively represents a negative mood state.

  As shown in Table 1, the lactoferrin drinking group (LLF) improves drowsiness when getting up, ease of sleeping, maintenance of sleep state, feeling of recovery from fatigue when waking up, and negative psychological state even in psychological state Showed results that are preventing you from becoming. On the other hand, in the placebo group, it was aggravated by the feeling of drowsiness and fatigue recovery at the time of getting up, and it was shown that there is a tendency to fall into a negative mental state. This study was conducted from the end of March to the beginning of June, but this period is the turn of the winter season when the sympathetic nerve is relatively strong and the summer season when the parasympathetic nerve is relatively strong. It is known that the physical condition and mental condition are most likely to be impaired throughout the year. In particular, in mental states, people fall into negative mental states in spring, seasonal affective disorder and depressive symptoms occur even in healthy people, and many people who develop mental illness or relapse in mentally ill history It is also known. The temperature and humidity of the tested period fluctuated in the range of 6.5 ° C., 58 RH% to 19.8 ° C., 72 RH% in the measurement data of the Japan Meteorological Agency (Osaka Prefecture). It is thought that the seasonal factors acted that the test results of the placebo group in this study showed a tendency to deteriorate sleep status and to get into negative mental status. Therefore, it can be inferred that the test results of the lactoferrin-drinking group have the effect of improving the sleep state and improving from a negative mental state to a positive mental state, considering the seasonal factors as well.

Examination of the effect of lactoferrin-containing liposome in mental condition after getting up As a test composition, Tablet A blended with lactoferrin-encapsulated liposome designed to be able to take 135 mg of lactoferrin at three tablets a day, and three tablets of lactoferrin at one day A tablet B containing lactoferrin designed so as to be able to be ingested 300 mg was prepared by the same method as described above and used for the test. The subjects analyzed the results with 33 persons except for the dropouts who used to think that they were living an irregular life mainly with shift workers whose working hours are not constant. In the test, the first week was a period during which the subject was not ingested, and the subsequent two weeks were periods during which the subject was ingested. The subject was defined as 3 daily particles, but the intake period and the intake method such as batch intake or divided intake were not limited at all and were left to the subject. The evaluation was conducted using the same "OSA Sleep Questionnaire MA version" as above when waking up every day during the 3 weeks of the test, and "I was tired" and "he was active" before going to bed. The survey was conducted using a Visual Analog Scale questionnaire for the four items that were clear and "concentrated." In addition, 17 subjects A and 16 subjects B were used for analysis, and the analysis of variance was used for the test. There were no significant differences between the two groups in all items during the non-drinking period. The evaluation results at the time of drinking are shown in FIGS.

As shown in the figure, significant differences were found between the two survey items: "I'm tired" (p 0.001 0.001) and "active" (p 0.001 0.001), and "the head was clear" “(P = 0.058)” and “there was concentration” (p = 0.091) showed a significant tendency.

Claims (4)

An oral composition for improving mental condition, which contains lactoferrin and exists in a state in which at least a part thereof is encapsulated in a liposome The oral composition for improving mental condition according to claim 1, which is present in a state in which more than half of the lactoferrin contained in the composition is contained in a liposome. The oral composition for mental condition improvement of any one of Claim 1 or 2 which contains the liposome which encloses lactoferrin as an active ingredient. The oral composition for mental condition improvement according to any one of claims 1 to 3, which is a pharmaceutical composition or a food composition.

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