Cerebral blood flow-increasing agent, brain activity-promoting agent, and awakening-improving agent

Abstract

The present invention relates to a cerebral blood flow increasing agent containing isomaltulose as an active ingredient.

Description

Technical Field

[0001] The present invention relates to an agent for increasing cerebral blood flow, an agent for promoting brain activity and an agent for improving wakefulness. Background Art

[0002] Isomaltulose is a compound also called 6-O-α-D-glucopyranosyl-D-fructose (trademark: PALATINOSE), and is known as a carbohydrate having various functionalities. For example, Patent Document 1 describes that the ingestion of isomaltulose can suppress the progression of diabetic nephropathy.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: Japanese Patent Application Publication No. 2016-41661

[0006] Non-patent literature

[0007] Non-patent document 1: Joel S. Warm et al., Vigilance requires hard mental work and is stressful, Human Factors, Vol. 50(3), pp. 433-41, 2008

[0008] Patent Document 2: Watson et al., The impact of blackcurrant juice on attention, mood and brain wave spectral activity in young healthy volunteers, NutritionalNeuroscience, Vol. 22(8), pp.596-606, 2019 Summary of the invention

[0009] Problems to be solved by the invention

[0010] The object of the present invention is to provide a new use of isomaltulose to further effectively utilize isomaltulose.

[0011] Means for solving problems

[0012] The inventors of the present application have found that isomaltulose has an effect of increasing cerebral blood flow, promoting brain activity, and improving the degree of wakefulness. The present invention is based on the above findings.

[0013] As one embodiment, the present invention provides a cerebral blood flow increaser, a brain activity promoter, or a wakefulness enhancer containing isomaltulose as an active ingredient. As described above, isomaltulose has cerebral blood flow increase, brain activity promoter, and wakefulness enhancer effects, and therefore, the above-mentioned preparation can increase cerebral blood flow, and with it, can promote brain activity and enhance wakefulness.

[0014] The present invention can also be understood as a method for increasing the cerebral blood flow of a subject, the aforementioned method comprising the step of administering an effective dose of a cerebral blood flow increasing agent containing isomaltulose as an active ingredient to a subject in need thereof. In addition, the present invention can also be understood as a method for promoting brain activity of a subject, the aforementioned method comprising the step of administering an effective dose of a brain activity promoter containing isomaltulose as an active ingredient to a subject in need thereof. In addition, the present invention can also be understood as a method for increasing the wakefulness of a subject, the aforementioned method comprising the step of administering an effective dose of a wakefulness enhancing agent containing isomaltulose as an active ingredient to a subject in need thereof.

[0015] The present invention can also be understood as the use of isomaltulose for the manufacture of a cerebral blood flow increasing agent. In addition, the present invention can also be understood as the use of isomaltulose for the manufacture of a brain activity promoting agent. In addition, the present invention can also be understood as the use of isomaltulose for the manufacture of an awakening enhancing agent.

[0016] The present invention can also be understood as isomaltulose for increasing cerebral blood flow. In addition, the present invention can also be understood as isomaltulose for promoting brain activity. In addition, the present invention can also be understood as isomaltulose for improving wakefulness.

[0017] Effects of the Invention

[0018] According to the present invention, a new use of isomaltulose is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [ Figure 1 ] is a graph showing the change of the reaction time of the subjects during DVT. The inter-group comparison was performed using the Bonferroni multiple comparison test.

[0020] [ Figure 2 ] is a graph showing the change in the average value of the cerebral blood flow change over time when the cerebral blood flow at the onset of DVT is set to 0.

[0021] [ Figure 3 ] is for Figure 2 The cerebral blood flow change amount during the transition of the average value of the cerebral blood flow change amount shown in FIG. 1 and the average value thereof were further calculated. The independent sample t-test method was used for comparison between the groups. DETAILED DESCRIPTION

[0022] The specific embodiments of the present invention are described in detail below, but the present invention is not limited to the following embodiments.

[0023] The cerebral blood flow increasing agent according to the present embodiment contains isomaltulose as an active ingredient.

[0024] Isomaltulose is a compound formed by α-1,6 bonding of glucose and fructose, and is also called 6-O-α-D-pyranosyl-D-fructose. In addition, isomaltulose is also called palatinose. Please note that "Palatinose / PALATINOSE" is a registered trademark of Mitsui Sugar Co., Ltd.

[0025] Isomaltulose is found in honey in nature. It is also present in the transfer products produced when α-glycosyltransferase (isomaltulose synthase) derived from bacteria and yeast acts on sucrose. In industry, isomaltulose is produced by allowing α-glycosyltransferase derived from bacteria such as Protaminobacter rubrum and Serratia plymuthica to act on sucrose.

[0026] As the isomaltulose used in the cerebral blood flow increasing agent, isomaltulose derived from nature may be used, or isomaltulose synthesized by the action of an enzyme or the like may be used.

[0027] Isomaltulose can be contained in the cerebral blood flow increasing agent in the form of crystals, or in the form of granular particles. Granular particles can be, for example, a collection of multiple crystals of isomaltulose and amorphous sugars, and the sugars are contained in the collection of crystals (spherical) particles. Such granular particles can be obtained, for example, by precipitating isomaltulose crystals from a sugar solution containing isomaltulose and amorphous sugars, and spray drying the sugar solution containing the crystals. Alternatively, it is also possible to precipitate isomaltulose crystal nuclei by heating the above-mentioned sugar solution while applying shear force to it, and cool the mixture containing the crystal nuclei, thereby obtaining granular particles containing isomaltulose. The above-mentioned sugar solution can be obtained, for example, by allowing an enzyme to act on sucrose. In this case, the sugar solution and the obtained granular particles contain trehalose, fructose, glucose, sucrose and isomaltulose as amorphous sugars. The granular particles may be solid substances described in Japanese Patent Application Laid-Open No. 2012-179045 or the like.

[0028] In addition, commercially available isomaltulose may be used. Commercially available products include, for example, crystalline palatinose (trade name "crystalline Palatinose PST-N", DM Mitsui Sugar Co., Ltd.), powdered palatinose (trade name "powdered Palatinose PST-NP", DM Mitsui Sugar Co., Ltd.), palatinose syrup (trade names "Palatinose Syrup-ISN" and "Palatinose Syrup-TN", DM Mitsui Sugar Co., Ltd.), and the like.

[0029] The cerebral blood flow increasing agent involved in the present embodiment has the effect of increasing cerebral blood flow (blood flow in the brain). "Increasing cerebral blood flow" can be to increase the blood flow of any part in the brain, for example, it can be to increase the blood flow of the dorsolateral prefrontal region responsible for learning, reasoning, inhibition, etc. With regard to the effect of increasing cerebral blood flow in this specification, it includes the effect of improving cerebral blood flow (the effect of restoring the reduced cerebral blood flow) and the effect of inhibiting the reduction of cerebral blood flow.

[0030] Cerebral blood flow can be measured based on near-infrared spectroscopy (fNIRS), which is a non-invasive optical imaging technique for monitoring the oxygenation state of tissues. fNIRS is a method of confirming changes in cerebral blood flow by irradiating the head with weak near-infrared light (650-1000nm) also contained in sunlight, so the measurement is highly safe and the device can be miniaturized. The measurement of cerebral blood flow using fNIRS can be performed, for example, by a portable brain activity measurement device (HOT-2000) manufactured by NeU Co., Ltd.

[0031] The cerebral blood flow increasing agent of this embodiment has the effect of promoting brain activity based on the effect of increasing cerebral blood flow. The effect of promoting brain activity in this specification includes the effect of improving brain activity (the effect of restoring decreased brain activity) and the effect of inhibiting decreased brain activity.

[0032] As for the cerebral blood flow increasing agent of the present embodiment, based on the effect of increasing cerebral blood flow, it has the effect of improving wakefulness. Wakefulness (alertness) refers to the ability to maintain attention for a long time and continue to pay attention to stimulation. As for the effect of improving wakefulness in this specification, it includes the effect of improving wakefulness (the effect of restoring the awakening that has decreased), the effect of inhibiting the decline of wakefulness, and the effect of maintaining a high state of wakefulness. In addition, the effect of improving wakefulness in this specification also includes the effect of a state in which the processing time, answer time or reaction time of a prescribed topic such as a cognitive topic are continuously processed for a long time.

[0033] The cerebral blood flow increasing agent of this embodiment has the effects of improving headaches, improving fatigue, improving anxiety, maintaining concentration, maintaining learning and office abilities, improving combat and physical functions during sports activities, and maintaining motivation for work based on the effect of increasing cerebral blood flow.

[0034] The cerebral blood flow increasing agent involved in this embodiment only needs to contain isomaltulose as an active ingredient, and may be formed of isomaltulose alone, or may be a composition containing isomaltulose. When the cerebral blood flow increasing agent is a composition, the isomaltulose contained therein may be contained in the form of isomaltulose monomer, or may be contained in the form of a commercially available isomaltulose preparation containing some sugars. Isomaltulose preparations sometimes contain other ingredients in addition to isomaltulose.

[0035] As other ingredients, materials that can be used in food, quasi-drugs or medicines can be used. There are no particular restrictions on the materials that can be used in food, quasi-drugs or medicines, and examples thereof include amino acids, proteins, carbohydrates, fats, sweeteners, minerals, vitamins, flavors, excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, suspending agents, and the like.

[0036] As proteins, casein, whey, soy protein, wheat protein, egg white, etc. can be mentioned. As carbohydrates, corn starch, cellulose, alpha starch, wheat starch, rice starch, potato starch, etc. can be mentioned. As fats and oils, salad oil, corn oil, soybean oil, safflower oil, olive oil, palm oil, etc. can be mentioned. As sweeteners, sugars such as glucose, sucrose, fructose, glucose-fructose syrup, fructose-glucose syrup can be mentioned; sugar alcohols such as xylitol, erythritol, maltitol, etc. can be mentioned; artificial sweeteners such as sucralose, aspartame, saccharin, acesulfame K, etc.; stevia sweeteners; etc. As minerals, calcium, potassium, phosphorus, sodium, manganese, iron, zinc, magnesium, etc., and their salts can be mentioned. As vitamins, vitamin E, vitamin C, vitamin A, vitamin D, vitamin B, biotin, niacin, etc. can be mentioned. As excipients, dextrin, starch, lactose, crystalline cellulose, etc. can be mentioned. As binders, polyvinyl alcohol, gelatin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, etc. can be mentioned. As lubricants, magnesium stearate, calcium stearate, talc, etc. can be mentioned. As disintegrants, crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, dextrin, etc. can be mentioned. As emulsifiers or surfactants, sucrose fatty acid esters, citric acid, lactic acid, glycerol fatty acid esters, polyglycerol fatty acid esters, sorbitol fatty acid esters, propylene glycol fatty acid esters, lecithin, etc. can be mentioned. As bases, cetearyl alcohol, lanolin, polyethylene glycol, etc. can be mentioned. As solubilizers, polyethylene glycol, propylene glycol, sodium carbonate, sodium citrate, etc. can be mentioned. As suspending agents, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxymethyl cellulose, sodium alginate, etc. can be mentioned. These ingredients can be used alone or in combination of two or more.

[0037] Isomaltulose has a sweetness of about 1 / 2 of that of sucrose. Therefore, the cerebral blood flow increasing agent involved in this embodiment can mainly contain isomaltulose as a sweetener. Since isomaltulose has a slow hydrolysis rate of 1 / 5 of that of sucrose, it can suppress the increase of blood sugar level after ingestion. Therefore, by making a substance mainly containing isomaltulose as a sweetener, the effect of making blood sugar control easier can also be obtained.

[0038] When the cerebral blood flow increasing agent contains ingredients other than isomaltulose, the content of isomaltulose can be appropriately set according to the form of the cerebral blood flow increasing agent, the purpose of use, etc., for example, based on the total amount of the cerebral blood flow increasing agent, it can be 10 mass% or more, 20 mass% or more, or 30 mass% or less, and can be 70 mass% or less, 60 mass% or less, or 50 mass% or less.

[0039] Cerebral blood flow increasing agent can be used as food composition or pharmaceutical composition. The food composition or pharmaceutical composition involved in the present embodiment can be provided in the form of health food, specific health food, functional food, nutritional functional food, supplement, quasi-drug, pharmaceutical product, etc. The food composition involved in the present embodiment can be attached with the purpose of increasing cerebral blood flow, promoting brain activity, and improving the purpose of awakening. In addition, the form of the agent can be any form of solid (powder, granules, etc.), liquid (solution, suspension, etc.), paste, etc., and can also be any dosage form of powder, pill, granule, tablet, capsule, lozenge, liquid, suspension, etc.

[0040] The cerebral blood flow increasing agent can be administered non-orally, but is preferably administered orally. As the dosage, for example, the dosage of isomaltulose per time can be more than 3g, more than 5g, more than 7g or more than 10g, can be less than 40g, less than 30g, less than 20g, less than 15g, less than 12g or less than 10g. In addition, the dosage of isomaltulose per day can be more than 3g, more than 5g or more than 10g, can be less than 40g, less than 30g or less than 20g. The cerebral blood flow increasing agent involved in the present embodiment can also play the desired effect even with less dosage than in the past. Isomaltulose is digested and absorbed more slowly than other sugars, so it has the characteristics of blood sugar level rising slowly and continuing for a long time higher than the state when fasting, and various functions are played based on this feature, but the cerebral blood flow increasing agent involved in the present embodiment still has the effect of increasing cerebral blood flow even with the dosage of the amount that is not easy to increase blood sugar level.

[0041] The cerebral blood flow increaser involved in this embodiment also has the effect of promoting brain activity and improving wakefulness, so the present invention can also be understood as a brain activity promoter or wakefulness enhancer containing isomaltulose as an effective ingredient. As a specific embodiment of the brain activity promoter or wakefulness enhancer, the embodiment described in the above-mentioned cerebral blood flow increaser can be applied.

[0042] As one embodiment of the present invention, there can be mentioned: a method for increasing the cerebral blood flow of a subject, the method comprising the step of administering an effective dose of a cerebral blood flow increasing agent containing isomaltulose as an active ingredient to a subject in need thereof; a method for promoting brain activity of a subject, the method comprising the step of administering an effective dose of a brain activity promoter containing isomaltulose as an active ingredient to a subject in need thereof; or a method for increasing the wakefulness of a subject, the method comprising the step of administering an effective dose of a wakefulness enhancing agent containing isomaltulose as an active ingredient to a subject in need thereof.

[0043] The subject in each of the above methods may be a mammal, preferably a human. The form, administration method, administration dose (ingestion amount), etc. of the cerebral blood flow increasing agent, brain activity promoting agent or wakefulness enhancing agent in each of the above methods may be the same as those described above.

[0044] As one embodiment of the present invention, there can be mentioned use of isomaltulose for producing an agent for increasing cerebral blood flow, use of isomaltulose for producing an agent for promoting brain activity, or use of isomaltulose for producing an agent for improving wakefulness.

[0045] The form of the cerebral blood flow increasing agent, brain activity promoting agent or awakening degree enhancing agent in each of the above uses may be the same as described above.

[0046] As one embodiment of the present invention, isomaltulose for increasing cerebral blood flow, isomaltulose for promoting brain activity, or isomaltulose for improving the degree of wakefulness can be mentioned.

[0047] Example

[0048] The present invention will be further described in detail below with reference to the following examples, but the present invention is not limited to these examples.

[0049] The effect of isomaltulose intake on cerebral blood flow and brain activity was evaluated by measuring the reaction time and cerebral blood flow changes in a cognitive task (Digit vigilance task (DVT)) of 64 healthy men and women aged 20 to 60. The specific test method is shown below.

[0050] <Test schedule>

[0051] The test was conducted on each subject based on the schedule shown in Table 1. In the test, each stage (block) including the process shown in Table 1 was implemented in 1 hour, and the first to fifth stages were implemented continuously on the same day. As shown in Table 1, a total of 5 DVTs were implemented in this test (details will be described later), and before the start of the second DVT, an aqueous solution obtained by dissolving 10.0g of isomaltulose in 100mL of water was ingested as a test meal. In addition, after the end of DVT and before the implementation of the next DVT, the Uchida Kraepelin test was implemented. The Uchida Kraepelin test is a test for the addition of adjacent single-digit numbers. In this test, it is implemented to impose fatigue and other loads on the subjects to coordinate the rest time.

[0052] [Table 1]

[0053]

[0054] <DVT>

[0055] DVT is mainly used for the purpose of measuring wakefulness (Non-patent document 1 (Joel S.Warm et al., Vigilance requires hard mental work and is stressful, Human Factors, Vol.50(3), pp.433-41, 2008)). In addition, DVT is also used to measure attention, mental fatigue, etc. (Non-patent document 2 (Watson et al., The impact of blackcurrant juice on attention, mood and brain wave spectral activity in young healthy volunteers, Nutritional Neuroscience, Vol.22(8), pp.596-606, 2019)). As a specific method, while the target number or character is always displayed on the right side of the screen, other numbers or characters are displayed in the center of the screen. The subject responds by operating the keyboard only when the number or character displayed in the center of the screen is consistent with the number or character displayed on the right side of the screen, and the time from the display of the number or character to the subject's response is measured. In this test, a prescribed number of tasks were performed continuously for 2 minutes, followed by a 30-second break, and this was repeated 6 times (total task time was 15 minutes).

[0056] <Questionnaire survey of subjects>

[0057] First, the subjects were asked, "Did you sleep better last night than usual?" After taking the DVT or Uchida-Kraepelin test, a subjective questionnaire survey was conducted on the subjects, asking questions such as "How is your current mood?", "Do you feel tired now?", "Do you feel anxious now?", "Do you feel sleepy now?", and "Did you participate in the project seriously until the end?" The questionnaire survey was conducted based on the VAS (Visual Analogue Scale) method, which is a method of indicating the relative position of the evaluation words at both ends.

[0058] <Control group>

[0059] The above subjects were allowed to take a test meal containing glucose instead of isomaltulose on another day, and the same test was carried out (crossover test), and this meal served as a control group.

[0060] <Evaluation>

[0061] [Evaluation of reaction time in DVT]

[0062] In DVT, the time from when a number or character is displayed in the center of the screen until the subject responds in accordance with the number or character displayed on the right side of the screen is measured, and the average reaction time of all subjects is calculated. Specifically, the average reaction time of each subject is calculated for the task repeated 6 times within the task time of 15 minutes, and the average reaction time of all subjects is further calculated. Figure 1 The figure shows how the average reaction time changes each time the number of DVTs is superimposed, when the average reaction time of the first DVT (implemented in the first stage) is set to 0. Figure 1 In the graph, a larger value of the reaction time shown on the vertical axis means that the reaction time is longer than that of the first DVT (reaction takes time).

[0063] like Figure 1 As shown, it can be seen that in the control group that took glucose, the reaction time when DVT was applied gradually became longer, while in the group that took isomaltulose, even if DVT was applied multiple times, the reaction time was not easy to become longer than that of the control group. That is, it can be said that by taking isomaltulose, the state of fast processing speed can be maintained for a longer time, and the state of high awakening can be maintained for a longer time. In addition, since DVT is also used to measure topics such as attention and mental fatigue, it can also be said that by taking isomaltulose, the state of high attention can be maintained for a long time and mental fatigue can be suppressed.

[0064] [Evaluation of cerebral blood flow]

[0065] Using a brain activity measurement device based on fNIRS (near infrared spectroscopy) (HOT-2000, manufactured by NeU Co., Ltd.), changes in cerebral blood flow in the dorsolateral prefrontal region during DVT were measured. This instrument can detect changes in hemoglobin concentration in the blood by irradiation with near infrared light, and as a result, changes in cerebral blood flow in active areas of the brain can be measured.

[0066] Figure 2 This is a graph showing the change in the average value of cerebral blood flow change over time when the average value of cerebral blood flow at the start of DVT is set to 0 in a total of 5 DVTs performed in the 1st to 5th stages. Figure 3 For Figure 2 The cerebral blood flow change amount during the transition of the average value of the cerebral blood flow change amount shown in FIG. 1 is the cerebral blood flow change amount during the time period from 0 seconds to 120 seconds, and the average value is further calculated. Figure 2 and Figure 3As shown, the group taking isomaltulose had a significantly greater change in cerebral blood flow through a total of 5 DVTs compared to the group taking glucose (control group). Therefore, it can be seen that compared to the case of taking glucose, the cerebral blood flow increases when taking isomaltulose, and as a result, brain activity is more active.

[0067] [Results of the questionnaire survey of the subjects]

[0068] After the project was completed, a questionnaire survey was conducted. In the questionnaire survey conducted in the third to fifth stages, the group that took isomaltulose answered "yes" compared to the control group. Therefore, it can be said that by taking isomaltulose, motivation for work can be maintained for a long time.

Claims

1. A cerebral blood flow increasing agent comprising isomaltulose as an active ingredient.

2. A brain activity promoter comprising isomaltulose as an active ingredient.

3. A wakefulness enhancing agent comprising isomaltulose as an active ingredient.

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