JP7777100B2 - Mood improvers - Google Patents

Description

The present disclosure relates to a mood-improving agent for healthy individuals, which contains collagen peptides.

Collagen is a structural protein found in skin, tendons, and cartilage. It is unique in that it contains repeating units of -(Gly-X-Y)n- (X and Y are any amino acids) and post-translationally modified hydroxyproline. Most collagens in vivo have a triple helix structure, consisting of three polypeptide chains with a molecular weight of approximately 100,000 bound together in a helix. When degraded with enzymes, acids, or alkalis, this yields polypeptides with chain lengths and compositions that vary depending on the degree of degradation and the enzyme. For example, when gelatin is degraded with a protease derived from Clostridium, it produces polypeptides whose main component is -(Gly-X-Y)n- (X and Y are any amino acids), and when it is degraded with an enzyme derived from ginger rhizome, it produces a peptide composition represented by the formula X-Hyp-Gly (X is an amino acid residue other than Gly, Hyp, or Pro) (Patent Document 1).

It has been reported that orally ingesting collagen peptides broken down by an enzyme derived from ginger rhizomes releases Pro-Hyp into the blood, which promotes the proliferation of hippocampal cells and exerts antidepressant-like effects (Non-Patent Document 1).

Furthermore, collagen peptides have been reported as DPP-4 inhibitors (Patent Document 2), immunostimulators (Patent Document 3), bone formation promoters (Patent Document 4), and angiotensin-converting enzyme inhibitors (Patent Document 5).

On the other hand, it is known that excessive work can cause various health problems, and the Ministry of Health, Labor and Welfare has set up a website where workers can self-check their accumulated fatigue levels (Non-Patent Document 2). Early detection of physical and mental fatigue can help avoid overwork, prevent lifestyle-related diseases and depression, and improve quality of life. There are also compositions for improving, maintaining, and/or improving attention function, which contain an enzymatic hydrolysate of whey protein containing a peptide with a specific amino acid sequence as an active ingredient (Patent Document 6), and foods for improving poor health that contain scallop mantle extract, improve vitality, suppress depression, and relieve fatigue (Patent Document 7).

Patent No. 6075656 International Publication No. 2013/065832 International Publication No. 2016/076276 Patent No. 6860877 Patent No. 7048270 Patent No. 7011984 Patent No. 7105456

“Prolyl-hydroxyproline, a collagen-derived dipeptide, enhances hippocampal cell proliferation, which leads to antidepressant-like effects in mice”, The FASEB Journal 34 (4), 5715-5723, 2020-03 Wiley https://kokoro.mhlw.go.jp/fatigue-check/worker.html

As mentioned above, there have been various reports on the efficacy of collagen peptides. Non-Patent Document 1 reports antidepressant effects, but the relationship between collagen peptides and the improvement of mental fatigue and poor physical condition described in Patent Documents 6 and 7 is unclear. Even healthy people with no problems with brain function can experience depression, not just those with dementia or depression. For example, fatigue can have both mental and physical causes, and mental fatigue manifests as somnolence (drowsiness) and lethargy. If it were possible to prevent or improve mental fatigue using collagen peptides derived from biological components, it would be safe, maintain and improve work efficiency, and improve the quality of life of each individual by improving mood.

In light of the above current situation, the present disclosure aims to provide an agent for improving the mood state of healthy people, a food product for improving fatigue in healthy people, and the like, which contains collagen peptides.

The present inventors administered collagen peptides degraded with microbial proteases to healthy individuals who are prone to illness for eight weeks, and evaluated their mood state using POMS2 (Profile of Mood States 2nd Edition) (trademark). They found that fatigue-lethargy (FI) and vigor-vitality (VA) scores improved with statistical significance compared to the placebo group, leading to the completion of this disclosure.

That is, the present disclosure provides an agent for improving fatigue and lethargy as assessed by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus, and Streptomyces .

Furthermore, the present invention provides an agent for improving vitality and energy as evaluated by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus, and Streptomyces .

According to the present disclosure , there is provided an agent for improving fatigue-lethargy and vitality-vigor as assessed by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus, and Streptomyces .

The present disclosure relates to an agent for improving fatigue-lethargy and vitality-vigor as assessed by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus, and Streptomyces . The present disclosure will be described in detail below.

The average molecular weight of the collagen peptides used in this disclosure is 500 to 12,000, preferably 1,000 to 10,000, more preferably 2,000 to 8,000, and particularly preferably 4,000 to 8,000. "Average molecular weight" refers to the weight-average molecular weight. Collagen has a "collagen-like sequence" represented by -(Gly-X-Y)n- (X and Y represent amino acids). It can be hydrolyzed with acid or alkali, and can also be degraded with microbial proteases such as those derived from Rhizopus, Aspergillus, Bacillus, and Streptomyces, as well as plant-derived proteases such as ginger rhizome enzyme. The peptide composition produced varies depending on the protease used. For example, Clostridium bacteria can produce collagen peptides primarily composed of the -(Gly-X-Y)n- (X and Y represent amino acids) sequence with an N-terminus of glycine by using enzymes specific for cleaving between Y and Gly. On the other hand, when collagen is hydrolyzed with an enzyme derived from ginger rhizome, peptide compositions can be obtained in which the second amino acid residue from the C-terminus is Pro or Hyp, such as X-Hyp-Gly, X-Pro-Gly, or Gly-Pro-X (where X is an amino acid residue other than Gly, Hyp, or Pro). The collagen peptides used in the present disclosure have been hydrolyzed with a microbial protease to achieve the above average molecular weight. Some low-molecular-weight collagen peptides are digestion-resistant and exhibit physiological activity when orally ingested. As described in Non-Patent Document 1, when ginger rhizome-derived enzyme hydrolyzates are ingested, Pro-Hyp is present in the blood, which affects brain function and exerts antidepressant effects. When the blood Pro-Hyp concentrations of humans who ingested 5 g of a ginger rhizome-derived enzymatic hydrolysate and a microbial protease hydrolysate were compared, the blood levels were 8.1 ± 5.4 nmol/ml for the ginger rhizome-derived enzymatic hydrolysate and 4.6 ± 3.0 nmol/ml for the microbial protease hydrolysate 30 minutes after ingestion, with a statistically significant difference (p < 0.05) for the microbial protease hydrolysate. The Area Under the Curve (AUC) up to 6 hours after ingestion was also statistically significantly lower (p < 0.05) for the microbial protease hydrolysate. However, as shown in the Examples below, the collagen peptides obtained by degradation with a microbial protease were found to improve mood state, as assessed by the internationally used POMS2™, in healthy individuals who are prone to fatigue and illness, thereby reducing fatigue and increasing vitality and energy.

The collagen peptides used in this disclosure may be derived from fish such as tilapia, sea bream, salmon, birds, pigs, cattle, or any other animal species, and may be extracted from any tissue such as fish scales, dermis, tendons, or bones. Preferably, they are derived from fish scales, pigs, cattle, or birds. Furthermore, while collagen types I to XXVIII are known, any type may be used. Type I collagen is preferred. The isoelectric point of collagen peptides varies depending on the production method, but in this disclosure, the isoelectric point is preferably 7.0 to 9.5, and more preferably 7.5 to 8.5.

In this disclosure, "healthy individuals" refers to individuals who are free from illness or disease and are in good physical and mental health. Furthermore, "mood state improvers" refer to agents that reduce fatigue and improve motivation and vitality.

The mood improvers, foods for improving fatigue in healthy people, and foods for improving and maintaining a positive mood in healthy people disclosed herein may contain added flavorings, excipients, thickeners, sweeteners, plant extracts, and vitamins, as long as their effects are not impaired. Furthermore, the dosage form may be any of powder, granules, pills, capsules, tablets, liquids, suspensions, and others, provided that the stability of the collagen peptides is ensured. In the case of powders or granules, they are preferably soluble in water or warm water and do not gel when the solution is cooled.

In this disclosure, food refers to an edible state that can be used directly for consumption by animals, including humans. Therefore, the food may be the above-mentioned food as is, or the food may be simply converted into a powder, granules, pellets, or other form. It may also be a liquid or jelly-like beverage made by adding water to the above-mentioned food, and optionally a thickener or flavoring agent, or a jelly made by solidifying the above-mentioned food with agar or gelatin.

The methods of administration of the foods disclosed herein for improving fatigue in healthy people and foods for improving and maintaining a positive mood in healthy people may include oral administration as well as tube administration. In this disclosure, "food" includes nutritional supplements such as supplements; nasal, enteral, and other tube-administered nutritional preparations. When used as a food, there are no particular restrictions on the other ingredients added to the food, provided that they are suitable for use as a food. Water, proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juice, flavors, and the like can be blended as ingredients.

Examples of nutritional supplements include the above foods as they are, or the above food compositions processed into powder, granules, pellets, etc., and liquid or jelly-like products obtained by adding water or a thickener to the above foods. The above food compositions may also be added to any of the conventionally known supplements.

The recommended daily intake, converted into the amount of collagen peptide, is 0.1 to 30 g, more preferably 2 to 10 g. Hydroxyproline is an amino acid characteristic of collagen, and when calculating the collagen peptide content, the amount of collagen peptide can be roughly calculated based on the amount of hydroxyproline. The dosage may be divided into multiple doses per day.

The mood improvers, foods for improving fatigue in healthy people, and foods for improving and maintaining a positive mood in healthy people disclosed herein may be taken before or after meals, between meals, or at any other time; they may be mixed into food ingredients and cooked, and the cooked ingredients may be ingested, or they may be sprinkled on cooked food ingredients and ingested.

The improvement agents, fatigue-improving foods for healthy people, and foods for improving and maintaining a positive mood in healthy people disclosed herein can maintain a healthy mood when administered to healthy people. They are also useful for people who suffer from mental fatigue caused by pressure, lethargy, or other mental fatigue, as well as healthy people who are prone to falling ill. Mental fatigue manifests as drowsiness, lethargy, etc. Preventing or improving mental fatigue can improve mood and enhance the quality of daily life.

The following examples will illustrate the present disclosure in more detail, but these examples are not intended to limit the present disclosure in any way.

Example 1
Evaluation was conducted in a randomized, placebo-controlled, double-blind, parallel-group comparative study using the Japanese version of POMS2, commissioned to Ortho Medico Co., Ltd. In addition to the 65 questions in POMS2, an original questionnaire using the Likert scale method and a diary-based physical condition questionnaire were also included.

The subjects for this experiment were healthy individuals aged 20 or over who fatigue easily and are prone to illness. They were selected from entrants with relatively high levels of fatigue-lethargy (FI) at screening. The subjects for analysis consisted of 31 individuals in each of the test food group and placebo group, and were divided into two groups to avoid significant differences in age, gender, height, and IgE levels. Analysis was performed using PPS (Per Protocol Analysis Set) and FAS (Full Analysis Set).

The subjects included: (i) those currently undergoing treatment for or with a history of malignant tumors, heart failure, or myocardial infarction; (ii) those with a pacemaker or implantable cardioverter defibrillator; (iii) those undergoing treatment for arrhythmia, liver damage, kidney damage, cerebrovascular disease, rheumatism, diabetes, dyslipidemia, hypertension, or other chronic diseases; (iv) those who regularly consume foods for specified health uses, foods with functional claims, or other foods/drinks that are thought to have functional properties; (v) those who eat foods high in lactic acid bacteria, such as lactic acid bacteria drinks and fermented foods, two or more days a week; and (vi) those who consume foods high in collagen/gelatin (beef tendon, liver, offal/hormones, pig's feet, chicken thighs, chicken wings/skin, chicken cartilage, fish). The following were excluded: (i) those who eat seafood (fish skin, conger eel, eel, monkfish, jelly, collagen hotpot, gelatin, gummy candy, marshmallows, etc.) more than two days a week; (vii) those who regularly take medicines (including herbal medicines) or supplements; (viii) those with allergies (to medicines or foods related to the test food), especially those who are allergic to fish, collagen, or gelatin; (ix) those who suffer from hay fever; (x) those who have received a vaccine for influenza or other infectious diseases within the year prior to the date of obtaining consent; (xi) those who are currently smoking or have quit smoking within the year prior to the date of obtaining consent; and (xii) those who are pregnant, breastfeeding, or intending to become pregnant during the study period.

The test drug used in the test food group was collagen peptide granules (trade name "FCP-AG", derived from tilapia type I collagen, digested with microbial food-grade proteases (derived from Rhizopus, Aspergillus, Bacillus, and Streptomyces), average molecular weight 4,000-8,000), and the placebo used in the placebo group was dextrin powder. Both groups took 5g twice a day (after breakfast and dinner) dissolved in about half a glass of water or warm water. The intake period was 8 weeks.

Participants were asked to answer 65 questions from the POMS2 at screening, at the start of intake (before intake), and four and eight weeks after intake. Responses were calculated for each item using seven scales: Tension-Anxiety (TA), Depression-Dejection (DD), Anger-Hostility (AH), Vigor-Activity (VA), Fatigue-Inertia (FI), Confusion-Bewilderment (CB), and Friendliness (F), and were evaluated using a Total Mood Disturbance (TMD) score.

Measurements at each time point were compared between groups using a linear mixed model with the screening value as the baseline value, and factors including covariates, time point, group, interaction between time point and group, interaction between baseline value and time point, and study participant.

The results of POMS2 were as follows:
(1) The actual measured values of fatigue and lethargy (FI) are shown in the table below. The test food group reduced FI values over time, but after 8 weeks of intake, the FI values were reduced more than the placebo group with a statistically significant difference (P = 0.045).

(2) The actual measured values for fatigue-lethargy (FI) are shown in the table below. The test food group improved their VA values over time, and after 8 weeks of intake, their VA values improved more than the placebo group with a statistically significant difference (P = 0.002).

(3) The actual measured values for POMS2, excluding FI and VA, at screening, at the start of intake, 4 weeks after intake, and 8 weeks after intake are shown below. The scores for TMD (Total Mood Disturbance), Anger-Hostility (AH), Confusion-Bewilderment (CB), Depression-Dejection (DD), and Tension-Anxiety (TA) showed a tendency for reduction over time, but no statistically significant differences were detected. Additionally, the score for Friendliness (F) fluctuated, and no statistically significant differences were detected.

In addition, an original Likert-scale questionnaire was administered at screening, at the start of intake, and after four and eight weeks of intake. The seven questions included: 1. "Shoulder stiffness and back pain," 2. "Tend to be constipated," 3. "Tend to have diarrhea," 4. "Fatigue persists even after a night's sleep," 5. "Feeling tired for no apparent reason," 6. "My skin is in poor condition," and 7. "My hands tend to get dry." Participants were asked to respond on a six-point scale: 1. "Not at all applicable," 2. "Not very applicable," 3. "Not very applicable," 4. "Somewhat applicable," 5. "Very applicable," and 6. "Very applicable." The median, first quartile (Q1), and third quartile (Q3) of the measured values were calculated and compared between groups using the Mann-Whitney U test. The results are shown in the table below. Eight weeks after the start of intake, a statistically significant difference (P<0.05) was detected between the placebo group and the test food group in the category of "I can't get rid of fatigue even after a full night's sleep."

In addition, a diary-style health questionnaire was conducted (1. "Feeling feverish," 2. "Runny nose," 3. "Nasal congestion," 4. "Sore throat," 5. "Cough," 6. "General fatigue," 7. "Muscle pain," 8. "Joint pain," 9. "Chills"). When the cumulative number of days each symptom occurred for each participant was compared between groups using a t-test, no statistical significance was detected for any of the symptoms.

(Summary)
Looking at the results for individual items in the test food group, at the time of testing after 8 weeks of intake, the sub-items of VA, "7. Lively,""12. Positive mood,""55. Feeling good without worries,""57.Energetic,""60.Motivated," and "62. Active," showed significantly higher scores compared to the placebo group, while the sub-items of FI, "45. Tired" and "59. Exhausted," showed significantly lower scores compared to the placebo group. Furthermore, in the original questionnaire, at the time of testing after 8 weeks of intake, the test food group showed significantly lower scores for "Fatigue doesn't go away even after a night's sleep" compared to the placebo group. These results suggest that ingestion of the test food attenuated mood states related to fatigue and lethargy, and enhanced mood states related to vitality and energy, as well as fatigue recovery through sleep, thereby reducing subjective fatigue and the onset of cold symptoms.

This disclosure allows for various embodiments and modifications without departing from the broad spirit and scope of the disclosure. Furthermore, the above-described embodiments are intended to explain the disclosure and do not limit the scope of the disclosure. In other words, the scope of the disclosure is defined by the claims, not the embodiments. Various modifications made within the scope of the claims and the meaning of equivalent disclosures are deemed to be within the scope of this disclosure.

Claims (2)

An agent for improving fatigue and lethargy as assessed by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus , and Streptomyces. An agent for improving vitality and vitality as evaluated by POMS2 in healthy individuals, which consists solely of collagen peptides having an average molecular weight of 2,000 to 8,000 that have been degraded with one or more proteases selected from the group consisting of Rhizopus, Aspergillus, Bacillus , and Streptomyces .