Autonomic balance regulator

Abstract

To find out which curcumin formulation is effective for varius symptoms caused by imbalance of autonomic nerve among existing various curcumin formulations.SOLUTION: An autonomic nerve balance regulator or a food composition for regulating autonomic nerve balance includes, as an active ingredient, an amorphous curcumin-containing composition that contains an admixture including (a) curcumin or turmeric pigment containing an amorphous matter, and a cellulose derivative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for regulating autonomic nervous balance. [Background technology]

[0002] The human body is able to perform the tasks necessary to sustain life, such as maintaining body temperature and breathing, sweating, and digesting food, through the work of the autonomic nervous system. The autonomic nervous system consists of two types of nervous systems: the sympathetic nervous system and the parasympathetic nervous system, which maintain a balance between them to regulate the body's condition. The sympathetic nervous system and the parasympathetic nervous system have opposing effects. The sympathetic nervous system is dominant during times of tension and excitement, increasing the heart rate, constricting blood vessels, raising blood pressure, suppressing gastrointestinal function, tensing muscles, and promoting sweating. On the other hand, the parasympathetic nervous system is dominant during times of relaxation, decreasing the heart rate, dilating blood vessels, lowering blood pressure, activating gastrointestinal function, relaxing muscles, and suppressing sweating. However, if this balance is disrupted for some reason, unpleasant symptoms occur. Examples include insomnia, fatigue, headaches, stiff shoulders, palpitations, shortness of breath, digestive symptoms such as stomach pain, diarrhea, and constipation, as well as irritability and anxiety. Causes of autonomic nervous system imbalance are said to include stress, seasonal changes, and menopausal disorders. However, even people who are considered healthy and do not have diseases such as menopausal disorders can experience various symptoms due to an imbalance in the autonomic nervous system.

[0003] Curcumin and its analogs have recently attracted attention for their physiological activities, such as antioxidant, anti-inflammatory, anti-allergic, tumorigenesis inhibitory, cholesterol-lowering, brain disease preventive, and cardiovascular disease preventive and therapeutic effects, and their use in feed, foods and beverages (e.g., functional foods), pharmaceuticals, cosmetics, etc. Curcumin is also known to inhibit monoamine oxidase (Non-Patent Document 1) and activate the dopaminergic nervous system (Non-Patent Document 2). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Pharmacogn.Mag.2016,12(Suppl 2),S116-20. [Non-patent document 2] Cardiovasc Psychiatry Neurol.2012;2012:942981 Summary of the Invention [Problem to be solved by the invention]

[0005] However, it is still unclear how effective curcumin is in treating imbalances in the autonomic nervous system. The objective of the present invention is to clarify which curcumin preparations are effective for various symptoms of autonomic nervous system imbalance, among the various curcumin preparations available. [Means for solving the problem]

[0006] Therefore, the present inventors conducted a randomized, placebo-controlled, double-blind, parallel-group comparative study using a specific amorphous curcumin-containing composition and found that the specific amorphous curcumin-containing composition induces a parasympathetic nervous system dominant state and is useful as an autonomic nervous system balance regulator or a food composition for regulating autonomic nervous system balance, thereby completing the present invention.

[0007] That is, the present invention provides the following [1] to [5]. [1] (a) An autonomic nervous system balance regulator or a food composition for regulating autonomic nervous system balance, which contains as an active ingredient an amorphous curcumin-containing composition containing a mixture of amorphous curcumin or turmeric pigment and a cellulose derivative. [2] The autonomic nervous system balance regulator or food composition for regulating autonomic nervous system balance according to [1], wherein the amorphous curcumin-containing composition (a) is (a-1) a composition containing solid curcumin or turmeric pigment including an amorphous body and a water-soluble cellulose derivative in a simply uniformly mixed state, or (a-2) a composition containing solid curcumin or turmeric pigment including an amorphous body, hydroxypropyl methylcellulose, and a non-gel-forming pharmaceutical additive in a simply uniformly mixed state. [3] An autonomic nervous balance regulator or a food composition for regulating autonomic nervous balance according to [1] or [2], wherein the autonomic nervous balance regulation induces a parasympathetic nervous dominant state. [4] An autonomic nervous balance regulator or a food composition for regulating autonomic nervous balance according to any one of [1] to [3], wherein the autonomic nervous balance regulation is an effect selected from a reduction in the profile score of the Profile of Mood States Questionnaire, Second Edition (POMS2) and a reduction in autonomic nervous function activity (LnLF and LF / HF) as a stress index. [5] The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance according to any one of [1] to [4], wherein the daily oral intake of curcumin for an adult is 90 mg to 300 mg. [Effects of the Invention]

[0008] Oral administration of the amorphous curcumin-containing composition of the present invention induces a parasympathetic dominant state, reduces the profile score of the Profile of Mood States Questionnaire, Second Edition (POMS2), and reduces autonomic nervous function activity (LnLF and LF / HF) as stress indicators, thereby regulating autonomic nervous balance and simultaneously improving both mental health and vascular function. The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance of the present invention is particularly useful for people who have not been diagnosed with autonomic nervous disorder but who are experiencing fatigue or stress. [Brief explanation of the drawings]

[0009] [Figure 1]The mean change from baseline in (A) LnLF and (B) LF / HF ratio during the study period in subjects aged 40 years or older is shown. Mean ± SD. LF: low frequency; HF: high frequency. DETAILED DESCRIPTION OF THE INVENTION

[0010] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0011] The autonomic nervous system balance regulator or food composition for regulating autonomic nervous system balance of the present invention has as its active ingredient a composition that stably contains amorphous curcumin, and one embodiment thereof is an autonomic nervous system balance regulator or food composition for regulating autonomic nervous system balance, the active ingredient of which is (a) an amorphous curcumin-containing composition that contains a mixture of curcumin or turmeric pigment containing an amorphous body and a cellulose derivative.

[0012] (a) Examples of the mixture containing amorphous curcumin or turmeric pigment and a cellulose derivative include (a-1) a composition containing amorphous solid curcumin or turmeric pigment and a water-soluble cellulose derivative in a simply uniformly mixed state, and (a-2) a composition containing amorphous solid curcumin or turmeric pigment, hydroxypropyl methylcellulose, and a non-gel-forming pharmaceutical excipient in a simply uniformly mixed state. A preferred example of a composition containing (a-1) a solid curcumin or turmeric pigment containing an amorphous form and a water-soluble cellulose derivative in a simply uniformly mixed state is a composition described in Japanese Patent No. 7072905, which contains (A) a solid curcumin or turmeric pigment containing an amorphous form and (B) one or more solid water-soluble polymers that become viscous in an aqueous medium of pH 5 or higher, selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and hydroxypropyl methylcellulose phthalate, in a simply uniformly mixed state, wherein the ratio (A-1) of the crystalline form of (A) curcumin or turmeric pigment to the amorphous form (A-2) (A-1 / A-2) is 0.67 or less. Here, the content mass ratio (A / B) of the curcumin or turmeric pigment (A) to the water-soluble cellulose derivative (B) is preferably 0.1 to 570, more preferably 0.5 to 50. Furthermore, the average particle size (d50) of each of the curcumin or turmeric pigment and the water-soluble cellulose derivative is preferably 300 μm or less.

[0013] (a-2) A composition containing a solid curcumin or turmeric pigment containing an amorphous substance, hydroxypropyl methylcellulose, and a non-gel-forming pharmaceutical excipient in a simply uniformly mixed state is, for example, a composition described in Japanese Patent No. 7080504, which contains (A) one or more selected from a solid curcumin or turmeric pigment containing an amorphous substance, and (B1) a 2% by mass aqueous solution of which viscosity at 20°C is 1 mm 2 / s or more 10mm 2 A preferred composition is a composition containing hydroxypropyl methylcellulose having a viscosity of not more than 1 / s and (C) a non-gel-forming pharmaceutical additive in a simply uniformly mixed state, wherein the mass ratio of component (C) to the sum of components (A) and (B1) (C / (A+B1)) is 0.4 to 7. Here, the mass ratio (A / B1) of the content of curcumin or turmeric pigment (A) to the content of hydroxypropylmethylcellulose (B1) is preferably 0.1 to 2. The non-gel-forming pharmaceutical additive may be one or more selected from the group consisting of non-gel-forming excipients, non-gel-forming disintegrants, non-gel-forming dispersants, non-gel-forming lubricants, non-gel-forming colorants, non-gel-forming flavors, and non-gel-forming flavoring agents. Examples of non-gel-forming excipients include one or more selected from the group consisting of lactose, fructose, crystalline cellulose, corn starch, dextrin, maltodextrin, isomalt, inositol, casein, fructose, xylitol, calcium citrate, citric acid hydrate, sodium citrate, refined sucrose, sorbitol, calcium carbonate, trehalose, potato starch, hydroxypropyl starch, glucose, partially pregelatinized starch, pullulan, pectin, povidone, maltose hydrate, mannitol, anhydrous citric acid, anhydrous sodium citrate, and anhydrous lactose. The non-gel-forming disintegrant may be one or more selected from the group consisting of dextrin, crospovidone, croscarmellose, croscarmellose sodium, crystalline cellulose, partially pregelatinized starch, and povidone. The non-gel-forming dispersing agent may be one or more selected from the group consisting of gum arabic, carrageenan, refined soybean lecithin, powdered tragacanth, and gum ghatti. The non-gel-forming lubricant may be one or more selected from the group consisting of magnesium stearate, calcium stearate, light anhydrous silicic acid, silicon dioxide, and talc. Non-gel-forming colorants include commonly used colorants, such as food dyes, caramel, and iron oxides. The non-gel-forming flavoring agent is a commonly used flavoring agent, such as various flavors and various extracts. Non-gel-forming flavoring agents are commonly used flavoring agents, such as ascorbic acids, citric acids, and various sweeteners.

[0014] As shown in the Examples below, oral administration of the amorphous curcumin-containing composition induces a parasympathetic nervous system-dominant state. Specifically, it reduces the profile score of the Profile of Mood States Questionnaire, Second Edition (POMS2) and the autonomic nervous function activity (LnLF and LF / HF) as stress indicators, thereby regulating autonomic nervous balance and simultaneously improving both mental health and vascular function. Therefore, the amorphous curcumin-containing composition is useful as an active ingredient of an autonomic nervous balance regulator and a food composition for regulating autonomic nervous balance. The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance of the present invention is particularly useful for people who have not been diagnosed with autonomic nervous system imbalance but who feel fatigue or stress.

[0015] The form of the autonomic nervous balance regulator or food composition for regulating autonomic nervous balance is preferably in the form of a typical composition for oral administration, and specific examples include powders, powders, granules, pills, capsules, tablets (including plain tablets, sugar-coated tablets, oral rapidly disintegrating tablets, chewable tablets, effervescent tablets, troches, film-coated tablets, etc.), dry syrups, films, and jellies. These forms can be prepared by appropriately blending the amorphous curcumin-containing composition with carriers, bases and / or additives commonly used in the pharmaceutical field within the scope of achieving the objectives of the present invention. For example, magnesium stearate, calcium stearate, etc. may be blended as a lubricant, and cornstarch, etc. may be blended as a space-filling agent. Also, it is preferable to use dextrin, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crystalline cellulose, etc., which act as disintegrants. Among these additives, the addition of a disintegrant is preferred, and it is more preferable to use dextrin, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, or crystalline cellulose.

[0016] The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance of the present invention can be taken orally on an ongoing basis due to the high safety of curcumin or turmeric pigment.

[0017] The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance of the present invention is preferably taken orally. The dosage can be varied appropriately depending on body weight, age, etc., but it is generally preferable to administer 90 mg to 300 mg of curcumin per day to an adult in one to three divided doses. [Example]

[0018] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples in any way.

[0019] Manufacturing Example 1 An appropriate amount of commercially available turmeric extract powder (curcumin content 86.8% (w / w)) was placed in a hot plate-type heating device and melted at a processing temperature of 220°C. The melted material was then kept at room temperature to solidify, and approximately 50 g of melt-processed curcumin (amorphous curcumin) was prepared. Next, the prepared melt-processed curcumin was powdered in a mortar and pestle, and the powder was passed through a sieve with 250 μm openings (10.0 g of melt-processed curcumin powder), 10.0 g of hydroxypropyl methylcellulose (HPMC), and 4.0 g of maltodextrin were simply mixed to prepare a powder.

[0020] Manufacturing Example 2 An appropriate amount of commercially available turmeric extract powder (curcumin content 86.8% (w / w)) was placed in a hot plate-type heating device and melted at a processing temperature of 220°C. The melted material was then kept at room temperature to solidify, and approximately 50 g of melt-processed curcumin (amorphous curcumin) was prepared. This was crushed in a mortar and sieved through a No. 30 sieve (10.0 g of melt-processed curcumin (amorphous curcumin) crushed product) and 2% by mass aqueous solution with a viscosity of 2.4 to 3.6 mm. 2 The mixture was prepared by simply mixing 10.0 g of hydroxypropyl methylcellulose (10.0 g / s) and 0.4 g of maltodextrin.

[0021] Test Example 1 (method) A randomized, double-blind, placebo-controlled, parallel-group comparative study was designed to investigate the effects of 12 weeks of ingestion of the composition of Manufacturing Example 2 (TS-P1) (150 mg / day as curcumin) on fatigue and mental state in 90 healthy Japanese adults. Fatigue and mood were assessed every 4 weeks (weeks 0, 4, 8, and 12) using the Visual Analogue Scale for Fatigue (VAS-F) and the Profile of Mood States Questionnaire, 2nd Edition (POMS2) (Kaneko Shobo, Tokyo, Japan). Autonomic nervous system balance and vascular function were assessed using accelerated plethysmography (APG).

[0022] (result) A total of 90 eligible subjects were selected and randomly assigned to either the placebo or TS-P1 group based on fatigue VAS-F scores, gender, age, and smoking status. There were no withdrawals or dropouts throughout the study. There were no significant differences in baseline fatigue, gender, age, or smoking status between the placebo and TS-P1 groups (Table 1).

[0023] [Table 1]

[0024] The results of the subanalysis of POMS2, APG and blood pressure are shown. In the subgroup of subjects aged 40 years or older, the mean change in depression / discouragement on POMS2 in the TS-P1 group showed a significant decrease at week 12. The mean change in LnLF in the TS-P1 group showed a greater decrease than in the placebo group after 4 weeks of supplementation. Because LnHF did not show a significant difference between the placebo and TS-P1 groups, the mean change in the LF / HF ratio tended to show a greater decrease throughout the study period (Figure 1). In addition, systolic blood pressure and diastolic blood pressure also decreased significantly in the TS-P1 group at 12 weeks, and the mean change in estimated vascular age decreased significantly in the TS-P1 group at 8 weeks, with the decrease expanding at 12 weeks. Weight and BMI also decreased significantly in the TS-P1 group at 8 and 12 weeks (Table 2). In Table 2, DD: depression / discouragement, EstAge: estimated vascular age, SBP: systolic blood pressure, DBP: diastolic blood pressure, Weight: body weight, BMI: obesity assessment.

[0025] [Table 2]

[0026] As shown in Figure 1 and Table 2, when assessed using the VAS-F, TS-P1 was not found to be effective against fatigue. However, the change in POMS2 DD in subjects aged 40 and over after 12 weeks of administration was lower in the TS-P1 group, indicating that TS-P1 is more effective in improving depressive symptoms. The effect of TS-P1 on this mood measurement suggests that it may be effective against fatigue, at least mental fatigue, which is thought to be related to brain inflammation. Because the VAS-F score is a subjective assessment that includes both mental and physical fatigue, quantitative objective assessment is necessary. Furthermore, in this study, the effects of TS-P1 were observed in subjects aged 40 years or older. Drug bioavailability is known to increase in the elderly due to changes in drug metabolism, and the same may have occurred with curcumin. It's also possible that people over 40 are more sensitive to stress and anger and may be more likely to detect mood changes. Autonomic nervous system balance is also known to be a factor affecting mood. In this study, heart rate variables were measured to evaluate the balance between the sympathetic and parasympathetic nervous systems. TS-P1 intake was observed to decrease or significantly decrease LnLF and LF / HF from baseline. These effects were more pronounced in people aged 40 years or older, suggesting that taking TS-P1 suppresses sympathetic nervous system activity and promotes parasympathetic nervous system dominance. Blood pressure was also significantly reduced by TS-P1, and vascular age estimated from the APG results was also significantly reduced from baseline in the TS-P1 group, suggesting that parasympathetic dominance also contributes to the maintenance of cardiovascular function. In this study, a significant decrease in the pulse wave b peak was observed, suggesting a reduction in afterload in healthy subjects, possibly due to an improvement in autonomic nervous balance.

Claims

1. (a) An autonomic nervous system balance regulator or a food composition for regulating autonomic nervous system balance, which has as an active ingredient an amorphous curcumin-containing composition containing a mixture of amorphous curcumin or turmeric pigment and a cellulose derivative.

2. The autonomic nervous system balance regulator or food composition for regulating autonomic nervous system balance according to claim 1, wherein the amorphous curcumin-containing composition (a) is either (a-1) a composition containing solid curcumin or turmeric pigment including an amorphous body and a water-soluble cellulose derivative in a simply uniformly mixed state, or (a-2) a composition containing solid curcumin or turmeric pigment including an amorphous body, hydroxypropyl methylcellulose, and a non-gel-forming pharmaceutical additive in a simply uniformly mixed state.

3. 2. The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance according to claim 1, wherein the autonomic nervous balance regulation induces a parasympathetic nervous dominant state.

4. The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance according to claim 1, wherein the autonomic nervous balance regulation is an effect selected from a reduction in the profile score of the Proof of Health Questionnaire, Second Edition (POMS2) and a reduction in autonomic nervous function activity (LnLF and LF / HF) as stress indicators.

5. The autonomic nervous balance regulator or food composition for regulating autonomic nervous balance according to any one of claims 1 to 4, wherein the daily oral intake amount for an adult is 90 mg to 300 mg in terms of curcumin.

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