Composition for treating menstrual accompanying symptoms

Abstract

The present invention relates to a composition for treating menstrual accompanying symptoms. Provided is a means for alleviating symptoms associated with menstruation by means of a food. In addition, the invention provides a new application of the lactobacillus paragasseri. Provided is a composition for treating menstrual accompanying symptoms, comprising lactic acid bacteria belonging to Lactobacillus paragasseri. The composition is particularly useful for any one of a symptom of physical discomfort before menstruation and a symptom of mental discomfort before menstruation.

Description

Technical Field

[0001] The present invention relates to a composition for treating symptoms associated with menstruation. Background Art

[0002] The Japanese Women's Active Participation Promotion Act was enacted in 2015 to promote women's participation in social activities. One of the major health issues for women is menstruation. Symptoms such as irritability, lower abdominal pain, irritability, headache, breast pain before menstruation, and lower abdominal pain during menstruation can reduce sleep quality when the degree is severe, and develop into various problems such as employment problems and adverse effects on childcare, sometimes causing adverse effects on the physical, mental, and social levels. In a survey report conducted by Tanaka et al. (Non-Patent Document 1) on approximately 20,000 Japanese menstruating women aged 15 to 49, it was reported that 74% of women were troubled by symptoms associated with menstruation, and the total economic loss was estimated to be approximately 682.8 billion yen per year. Therefore, the symptoms associated with menstruation hinder women's work and studies, which is a big problem. On the other hand, only 20% of women have a history of treatment, and many of them respond by using commercially available analgesics (Non-Patent Document 1).

[0003] Some ingredients effective for treating symptoms associated with menstruation have been studied. For example, Patent Document 1 provides a composition for treating symptoms associated with menstruation containing α-lactalbumin.

[0004] On the other hand, Lactobacillus gasseri / paragasseri is known to be a resident lactic acid bacteria species in the intestines of healthy people. Previous studies have shown that Lactobacillus paragasseri can be used as an active ingredient in a food and beverage composition for preventing or improving both or either of endometriosis (Patent Document 2), and can also be used as an active ingredient in a stress reliever (Patent Document 3).

[0005] Furthermore, agents for alleviating premenstrual physical and / or mental discomfort symptoms (Patent Document 4, Non-Patent Document 2) and agents for improving female menopausal symptoms (Patent Document 5) containing the lactic acid bacteria strain Lactobacillus gasseri CP2305 (Accession No.: FERM BP-11331), processed products of the above lactic acid bacteria strain, or extracts thereof have been studied.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication WO2019 / 235451

[0009] Patent Document 2: International Publication No. WO2012 / 073924

[0010] Patent Document 3: International Publication No. WO2014 / 132982

[0011] Patent Document 4: International Publication No. WO2021 / 015104

[0012] Patent Document 5: Japanese Patent Application Publication No. 2022-113373

[0013] Non-patent literature

[0014] Non-patent literature 1: Tanaka E, Momoeda M, Osuga Y, et al. Burden of menstrualsymptoms in Japanese women: results from a survey-based study. J Med Econ 2013:16:1255-1266.

[0015] Non-patent literature 2: Nishida K, et al. Daily intake of Lactobacillus gasseriCP2305 ameliorates psychological premenstrual symptoms in young women: Arandomized, double-blinded, placebo-controlled study. J Functional Foods 2021:80:104426 Summary of the invention

[0016] Problem that the invention aims to solve

[0017] If there is a means to relieve the symptoms associated with menstruation through food, it is considered to be useful for improving women's quality of life (QOL; Quality of Life).

[0018] Solutions for solving problems

[0019] The present inventors have conducted in-depth research on Lactobacillus paragaseri. Among them, they have conducted research based on the assumption that the use of this strain can also be effective for symptoms associated with menstruation, and have completed the present invention. The present invention provides the following solutions.

[0020] [1] Use of lactic acid bacteria belonging to Lactobacillus paragasseri or a composition containing lactic acid bacteria belonging to Lactobacillus paragasseri for non-disease therapeutic purposes of treating symptoms associated with menstruation.

[0021] [2] The use according to item 1, wherein the menstrual symptoms are any of premenstrual physical discomfort symptoms and premenstrual mental discomfort symptoms.

[0022] [3] The use according to 1 or 2, wherein the menstrual symptoms are symptoms of mental discomfort before menstruation.

[0023] [4] The use according to any one of 1 to 3, which is for ingestion by a subject who is not suffering from menopausal symptoms or a subject in adolescence or sexual maturity.

[0024] [5] The use according to any one of 1 to 4, wherein the symptoms associated with menstruation are selected from symptoms of mental discomfort, and the symptoms of mental discomfort are one or more of irritability, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm.

[0025] [6] Use of Lactobacillus paragaseri or a composition comprising Lactobacillus paragaseri for non-disease therapeutic purposes of controlling premenstrual hyperactivity.

[0026] [7] Use of Lactobacillus paragaseri or a composition comprising Lactobacillus paragaseri for non-disease therapeutic purposes of controlling premenstrual irritability.

[0027] [8] The use according to any one of 1 to 7, wherein the Lactobacillus paragaseri is a heated bacterial cell; or the composition contains the Lactobacillus paragaseri in the form of heated bacterial cells.

[0028] [9] The use according to any one of 1 to 8, wherein only Lactobacillus paragaseri is used as an active ingredient; or the composition contains only Lactobacillus paragaseri cells as an active ingredient.

[0029]

[10] The use according to any one of 1 to 9, wherein the Lactobacillus paragaseri is Lactobacillus paragaseri OLL2809 deposited under the accession number NITE BP-72, or a strain taxonomically equivalent thereto.

[0030]

[11] The use according to any one of 1 to 10, for providing 1×10 8 ~1×10 12 or a composition for ingesting 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

[0031]

[12] A use for non-disease therapeutic purposes for treating symptoms associated with menstruation, comprising the step of causing a subject to ingest lactic acid bacteria belonging to Lactobacillus paragaseri or a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri.

[0032]

[13] The use according to item 12, wherein the daily intake is 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

[0033] [1] A composition for treating symptoms associated with menstruation, comprising lactic acid bacteria belonging to the genus Lactobacillus paragasseri.

[0034] [2] The composition according to item 1, wherein the symptoms associated with menstruation are any of premenstrual physical discomfort symptoms and premenstrual mental discomfort symptoms.

[0035] [3] The composition according to 1 or 2, wherein the menstrual symptoms are symptoms of premenstrual mental discomfort.

[0036] [4] The composition according to any one of 1 to 3, which is for ingestion by a subject who is not suffering from menopausal symptoms or a subject in adolescence or sexual maturity.

[0037] [5] The composition according to any one of 1 to 4, wherein the menstrual symptoms are symptoms of mental discomfort, and the symptoms of mental discomfort are one or more selected from irritability, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm.

[0038] [6] A composition for controlling premenstrual hyperactivity, comprising Lactobacillus paragaseri.

[0039] [7] A composition for controlling premenstrual irritability comprising Lactobacillus paragaseri.

[0040] [8] The composition according to any one of 1 to 7, wherein the Lactobacillus paragaseri is contained in the form of heated bacterial cells.

[0041] [9] The composition according to any one of 1 to 8, wherein the active ingredient is only the bacterial cells of Lactobacillus paragaseri.

[0042]

[10] The composition according to any one of 1 to 9, wherein the Lactobacillus paragaseri is Lactobacillus paragaseri OLL2809 deposited under the accession number NITE BP-72, or a strain taxonomically equivalent thereto.

[0043]

[11] The composition according to any one of 1 to 10, for use in a daily intake of 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

[0044]

[21] A composition containing lactic acid bacteria belonging to Lactobacillus paragaseri for use in a method for treating symptoms associated with menstruation. Use of lactic acid bacteria belonging to Lactobacillus paragaseri in the manufacture of a composition for treating symptoms associated with menstruation. A method or non-therapeutic method for treating symptoms associated with menstruation comprising the step of administering a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri to a subject. Use or non-therapeutic use of a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri for treating symptoms associated with menstruation.

[0045]

[22] The composition, use in manufacturing, method or non-therapeutic method or use or non-therapeutic use according to 21, wherein the menstrual symptoms are any of pre-menstrual physical discomfort symptoms and pre-menstrual mental discomfort symptoms.

[0046]

[23] The use, method or non-therapeutic method or use or non-therapeutic use in the manufacture according to 21 or 22, wherein the menstrual associated symptoms are symptoms of mental discomfort before menstruation.

[0047]

[24] The composition, use in manufacturing, method or non-therapeutic method or use or non-therapeutic use according to any one of 1 to 3, wherein the composition is for ingestion by a subject who is not suffering from menopausal symptoms or a subject in adolescence or sexual maturity.

[0048]

[25] The composition, use in manufacturing, method or non-therapeutic method or use or non-therapeutic use according to any one of 21 to 24, wherein the menstrual associated symptoms are symptoms of mental discomfort, and the symptoms of mental discomfort are one or more selected from irritability, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm.

[0049]

[26] A composition containing lactic acid bacteria belonging to Lactobacillus paragaseri for use in a method for controlling premenstrual hyperactivity. Use of lactic acid bacteria belonging to Lactobacillus paragaseri in the manufacture of a composition for controlling premenstrual hyperactivity. A method or non-therapeutic method for controlling premenstrual hyperactivity comprising the step of administering a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri to a subject. Use or non-therapeutic use of a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri for controlling premenstrual hyperactivity.

[0050]

[27] A composition comprising lactic acid bacteria belonging to Lactobacillus paragaseri for use in a method for controlling premenstrual irritability. Use of lactic acid bacteria belonging to Lactobacillus paragaseri in the manufacture of a composition for controlling premenstrual irritability. A method or non-therapeutic method for controlling premenstrual irritability comprising the step of administering a composition comprising lactic acid bacteria belonging to Lactobacillus paragaseri to a subject. Use or non-therapeutic use of a composition comprising lactic acid bacteria belonging to Lactobacillus paragaseri for controlling premenstrual irritability.

[0051]

[28] The composition, use in manufacture, method or non-therapeutic method or use or non-therapeutic use according to any one of 21 to 27, wherein the Lactobacillus paragaseri is contained in the form of heated bacteria.

[0052]

[29] The composition, use in production, method or non-therapeutic method or use or non-therapeutic use according to any one of 21 to 28, wherein only the bacteria of Lactobacillus paragaseri are used as the active ingredient.

[0053]

[30] The composition, use in manufacture, method or non-therapeutic method or use or non-therapeutic use according to any one of 21 to 29, wherein the Lactobacillus paragaseri is Lactobacillus paragaseri OLL2809 deposited under the accession number NITE BP-72 or a strain taxonomically equivalent thereto.

[0054]

[31] The composition, use in manufacturing, method or non-therapeutic method or use or non-therapeutic use according to any one of 21 to 30, wherein the composition is used for taking 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

[0055] Effects of the Invention

[0056] The composition containing lactic acid bacteria belonging to Lactobacillus paragaseri can be used to treat symptoms associated with menstruation. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 For the test schedule.

[0058] Figure 2 is a flow chart showing the flow of subjects at each stage.

[0059] Figure 3 The graph shows the temporal changes in the premenstrual MDQ "hyperactivity" score adjusted for explanatory variables (group, analgesic use score, stress level score, exercise habits). Error bars indicate 95% confidence intervals.

[0060] Figure 4Change from baseline in the premenstrual MDQ “hyperactive mood” symptom category score during the third menstrual cycle (Mean±SE).

[0061] Figure 5 The graph shows the temporal changes in the premenstrual VAS "Impatient" score adjusted for the explanatory variables (group, analgesic use score, stress level score, exercise habits). The error bars represent the 95% confidence interval.

[0062] Figure 6 It is the 16s rRNA gene of Lactobacillus paragaseri OLL2809 (SEQ ID NO: 1). DETAILED DESCRIPTION

[0063] The present invention relates to the use of lactic acid bacteria belonging to Lactobacillus paragasseri for treating symptoms associated with menstruation and a composition for the same. It should be noted that, for the present invention, embodiments, and examples, a composition containing specific lactic acid bacteria is used as an example for description, but the description is also applicable to the purpose, method of use, etc. of the lactic acid bacteria.

[0064] [Active ingredients]

[0065] (Lactobacillus paragaseri)

[0066] The composition of the present embodiment uses lactic acid bacteria belonging to Lactobacillus paragaseri as an active ingredient. The lactic acid bacteria can be any specific strain. For the present invention, when referred to as "any", it is used in the sense of "at least one" unless otherwise specified. "Using as an active ingredient" means: using it in an effective amount to exert the target function, specifying its use by being labeled as a component that contributes to the target, etc. In the present invention, when describing the bacteria belonging to the genus Lactobacillus, except for the cases otherwise described, the classification is based on the reclassification of Zheng J, Wittouck S, Salvetti E, Franz CMAP, Harris HMB, Mattarelli P, O'Toole PW, Pot B, Vandamme P, Walter J, Watanabe K, Wuyts S, FelisGE, Ganzle MG, Lebeer S.: A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. Int J Syst Evol Microbiol. 2020Apr;70(4):2782-2858.

[0067] Lactobacillus paragaseri is a Gram-positive bacterium that performs homolactic fermentation. T Lactobacillus paragasseri and Lactobacillus gasseri can be distinguished by average nucleotide similarity (ANI) or DNA-DNA hybridization. Examples of lactic acid bacteria strains belonging to Lactobacillus paragasseri include JCM 5343 T , Lactobacillus paragaseri OLL2809 (NITE BP-72), FERM BP-6999 and NITE BP-224.

[0068] Strains with numbers beginning with JCM can be purchased from the Microbial Materials Development Laboratory, RIKEN Bioresource Research Center (3-1-1 Konodai, Tsukuba, Ibaraki 305-0074, Japan). Strains with numbers beginning with NITE can be obtained from the Patent Microorganism Collection of the National Institute for Evaluation and Technology for Products (Room 122, 2-5-8 Kazusa Kamata, Kisarazu, Chiba, Japan). Strains with numbers beginning with FERM can be obtained from the Patent Microorganism Collection of the National Institute for Evaluation and Technology for Products (Room 120, 2-5-8 Kazusa Kamata, Kisarazu, Chiba, Japan).

[0069] In a preferred embodiment, the composition contains Lactobacillus paragaseri OLL2809 or a bacteriologically equivalent strain thereof as an active ingredient. As described below, Lactobacillus paragaseri OLL2809 is particularly effective in treating premenstrual discomfort among menstrual symptoms.

[0070] (Lactobacillus paragaseri OLL2809)

[0071] Lactobacillus paragaseri OLL2809 was deposited internationally under the Budapest Treaty under the accession number NITE BP-72.

[0072] Depositor: Meiji Co., Ltd.

[0073] Depository: National Institute of Technology for Product Evaluation Patent Microorganisms Depository Accession number: NITE BP-72

[0074] Original date of preservation: February 1, 2005

[0075] Date of transfer to the deposit under the Budapest Treaty: January 18, 2006

[0076] It should be noted that when strain OLL2809 was deposited, it was recorded as Lactobacillus gasseri according to the classification at the time of the deposit. Since 2018, the academic community has specifically split Lactobacillus gasseri into Lactobacillus gasseri and Lactobacillus paragasseri. In this context, the applicant clarified that strain OLL2809, which was deposited as Lactobacillus gasseri with the deposit number NITE BP-72, should actually be classified as Lactobacillus paragasseri.

[0077] The sequence of the 16S rRNA gene of Lactobacillus paragaseri OLL2809 (total length 1580 bases) is shown in Figure 6 and sequence number 1 of the sequence listing.

[0078] The sequence of sequence number 1 derived from Lactobacillus paragasseri and the sequence of the 16S rRNA gene of Lactobacillus gasseri (sequence number: NR_075051.2) have a sequence identity of 99.24% (1568 / 1580 identical). In one embodiment, the sequence of the 16S rRNA gene of Lactobacillus paragasseri contained in the composition has a sequence identity of 99.25% or more, preferably 99.3% or more, more preferably 99.35% or more, further preferably 99.4% or more, further preferably 99.45% or more, further preferably 99.5% or more, further preferably 99.55% or more, further preferably 99.6% or more, further preferably 99.65% or more, further preferably 99.7% or more, further preferably 99.75% or more, further preferably 99.8% or more, further preferably 99.85% or more, further preferably 99.9% or more, further preferably 99.95% or more, further preferably 100%.

[0079] The bacteriological properties of Lactobacillus paragaseri OLL2809 are shown below.

[0080] Colony characteristics on culture medium (Lactobacilli MRS Agar, DIFCO): 2-3 mm in diameter, light yellow, round, flat, with neat edges, smooth, opaque, and viscous

[0081] Bacterial form: Bacillus

[0082] Gram stain: positive

[0083] Lactic acid fermentation form: homolactic fermentation

[0084] Aerobic growth: +

[0085] Growth temperature: 15℃-, 45℃+

[0086] Sugar fermentability: arabinose-, xylose-, rhamnose-, ribose-, glucose+, mannose+, fructose+, galactose+, sucrose+, cellobiose+, lactose+, trehalose+, melezitose-, raffinose-, melezitose-, mannitol-, sorbitol-

[0087] The strain that is taxonomically equivalent to a certain strain (hereinafter referred to as strain S) refers to any of the following, for example.

[0088] · Its 16S rRNA gene (hereinafter sometimes referred to as "16S", "16S rRNA gene".) having a sequence identity of 97% or more, more preferably 98% or more, further preferably 98.5% or more, further preferably higher than 98.7% with the sequence of strain S; a strain having a sequence identity of further preferably 99% or more, further preferably 99.25% or more, further preferably 99.3% or more, further preferably 99.35% or more, further preferably 99.4% or more, further preferably 99.45% or more, further preferably 99.5% or more, further preferably 99.55% or more, further preferably 99.6% or more, further preferably 99.65% or more, further preferably 99.7% or more, further preferably 99.75% or more, further preferably 99.8% or more, further preferably 99.85% or more, further preferably 99.9% or more, further preferably 99.95% or more, further preferably 100%;

[0089] · Strains with the same bacteriological properties as strain S.

[0090] A strain that is a mutant or derivative of strain S and has the effect of treating symptoms associated with menstruation.

[0091] With regard to the present invention, sequence identity refers to the ratio of the number of consistent bases shared between sequences when two sequences are arranged in an optimal manner when no special statement is made. Regarding the identity analysis of base sequences, algorithms or programs (such as BLASTN, BLASTP, BLASTX, ClustalW) well known to those skilled in the art can be used. The parameters when using the program can be appropriately set by those skilled in the art, and in addition, the default parameters of each program can be used. The specific operation of these analytical methods is also well known to those skilled in the art. The calculation of identity can also use commercially available gene information processing software.

[0092] It should be noted that, regarding the criteria for judging the differences and similarities between species based on 16S rRNA gene sequences, those skilled in the art may refer to Stackebrandt E, Ebers J. Taxonomic parameters revisited: tarnished gold standards. Microbiol Today 2006; 33: 152-155.

[0093] (Other active ingredients)

[0094] In one embodiment, the active ingredient in the composition is only the bacterial body of lactic acid bacteria belonging to Lactobacillus paragaseri, for example, only the bacterial body of Lactobacillus paragaseri OLL2809 or a strain equivalent thereto in taxonomy. That is, in one embodiment, the composition does not contain other components known to be effective for the treatment of symptoms associated with menstruation other than the bacterial body of lactic acid bacteria belonging to Lactobacillus paragaseri, for example, it does not contain α-lactalbumin in an amount clinically effective for the treatment of symptoms associated with menstruation. When the composition contains α-lactalbumin, an amount less than the amount clinically effective for the treatment of symptoms associated with menstruation refers to an amount less than 100 mg per meal, for example, 50 mg or less, 25 mg or less, 20 mg or less, 10 mg or less, 5 mg or less, 3 mg or less, 2 mg or less, 1 mg or less, 0.5 mg or less, 0.3 mg or less, 0.2 mg or less, 0.1 mg or less.

[0095] (Manufacturing method)

[0096] The lactic acid bacteria belonging to Lactobacillus paragaseri contained in the composition can be produced by culturing. The culturing conditions are not particularly limited as long as the target effect can be exerted.

[0097] The lactic acid bacteria belonging to Lactobacillus paragaseri may be contained in any state in the composition as long as the target effect is exerted. For example, the lactic acid bacteria may be lactic acid bacteria cells themselves or may be lactic acid bacteria cultures (including lactic acid bacteria cells and culture supernatant).

[0098] The culture of lactic acid bacteria can be obtained by conventional methods for preparing the culture of lactic acid bacteria. In the culture, various culture media such as milk culture medium or culture medium containing milk components, semi-synthetic culture medium not containing these, synthetic culture medium, etc. can be used. The culture of lactic acid bacteria can be obtained by inoculating lactic acid bacteria belonging to Lactobacillus paragaseri into the above-mentioned culture medium after sterilization and culturing at about 20°C to 45°C for 5 hours to several days. The temperature and time of cultivation can be appropriately adjusted according to the lactic acid bacteria strain belonging to Lactobacillus paragaseri used and the desired number of bacteria. The culture can be used directly or after the culture is subjected to treatments such as centrifugation, membrane concentration, drying, freeze drying, and washing.

[0099] The bacteria can be in a living state (live bacteria) or a dead state (dead bacteria) as long as they can exert the target effect.

[0100] Dead bacteria can be obtained by sterilizing lactic acid bacteria. Sterilization is not particularly limited as long as it can exert the target effect, and heating, sterilizing lamp (UV), ozone, medicament, high osmotic pressure, etc. can be used. Dead bacteria are preferably heat-treated dead bacteria obtained by heat-treating live bacteria. The heat treatment used to obtain heat-treated dead bacteria is not particularly limited as long as it can exert the target effect, and is implemented at a temperature and time sufficient to kill the lactic acid bacteria used. Such conditions also depend on the lactic acid bacteria used, for example, it can be above 55°C, preferably above 60°C, more preferably above 65°C, and further preferably above 70°C, and can be set to above 80°C, and can be set to above 90°C. The upper limit of the heat treatment temperature can be set to an appropriate value, for example, below 121°C, below 100°C, below 90°C, and below 80°C. In addition, according to the heat treatment temperature, the heat treatment time can be set to more than 1 minute, can be set to more than 3 minutes, can be set to more than 10 minutes, more than 15 minutes, more than 30 minutes, and more than 45 minutes. The upper limit of the heat treatment time may be, for example, 120 minutes or less, 100 minutes or less, 90 minutes or less, or 80 minutes or less.

[0101] Regardless of whether the lactic acid bacteria to be included in the composition are live or dead bacteria, they can be prepared in the form of bacteria washes, concentrates, dry products, suspensions, pastes, gels, and the like.

[0102] [use]

[0103] (Functions, effects, etc.)

[0104] The composition of the present embodiment can be used to treat symptoms associated with menstruation. Treatment includes: inhibiting, blocking or reducing the onset / appearance (occurrence) of the disease or state that becomes the object, reducing its onset / occurrence risk; treating the onset / occurrence of the disease or state that becomes the object; inhibiting, blocking or delaying the progression of the disease or state that becomes the object. Treatment includes: medical actions performed by doctors and nurses, midwives, etc. who receive doctors' instructions; and non-therapeutic actions performed by people other than doctors, such as pharmacists, nutritionists (including management nutritionists, sports nutritionists), health workers, midwives, caregivers, clinical examination technicians, sports instructors, drug manufacturers, drug sellers, food manufacturers, food sellers, etc. Treatment also includes: recommending the intake of specific foods and nutritional guidance (including nutritional guidance required for the recuperation of the injured and sick and nutritional guidance for maintaining and promoting health).

[0105] Menstrual symptoms are a general term for uncomfortable symptoms associated with menstruation, including uncomfortable symptoms before and during menstruation. Menstrual symptoms include premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). PMS is defined as "mental or physical symptoms that last 3 to 10 days before menstruation and subside or disappear with the onset of menstruation." In PMS, if mental symptoms are predominant, it is diagnosed as premenstrual dysphoric disorder (PMDD). PMDD is characterized by four main symptoms: depression, anxiety and tension, emotional instability, and anger and irritability. Characteristic symptoms such as changes in eating behavior and sleep disorders appear before menstruation, thus affecting social activities and interpersonal relationships, but its cause and condition are not yet fully understood. It eases or disappears with the onset of menstruation.

[0106] In the present invention, unless otherwise specified, premenstrual period refers to the period from 7 days before the expected menstrual period to the day before the menstrual period begins. Premenstrual period can also be expressed in another way, that is, the period of elevated body temperature from ovulation to before the menstrual period (high temperature period). Although there are individual differences in body temperature, the high temperature period usually shows a rise of about 0.3 to 0.5°C.

[0107] Symptoms associated with menstruation can be distinguished from symptoms of female menopause. Symptoms associated with menstruation are symptoms that appear temporarily before or during menstruation in accordance with the sexual cycle, and the symptoms weaken or disappear as the menstrual period passes, while symptoms of female menopause do not have the same cyclical nature as symptoms associated with menstruation. In addition, as described below, subjects with symptoms associated with menstruation and subjects with symptoms of female menopause can also be distinguished as subjects.

[0108] Whether a certain ingredient can be used to treat menstrual symptoms can be evaluated by using the Menstual Distress Questionaire (MDQ) (Moos RH. The development of amenstrual distress questionnaire. Psychosom Med 1968: 30: 853-867.) In addition, it can also be evaluated by using the Visual Analog Scale (VAS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) together with the MDQ.

[0109] Specifically, the MDQ is a 46-item self-report questionnaire used to evaluate and treat premenstrual and menstrual symptoms. The 46 items are divided into the following 8 sub-factors: (1) pain, (2) water retention, (3) changes in the autonomic nervous system, (4) negative emotions, (5) decreased concentration, (6) behavioral changes, (7) hyperactivity, and (8) control. Among these sub-factors, only (7) hyperactivity is an item that can be considered a positive change.

[0110] In addition, the SF-36 can be used to evaluate health-related QOL. More specifically, the SF-36 can be used to score eight subscales: (1) physical function, (2) daily work function (physical), (3) bodily pain, (4) overall sense of health, (5) vitality, (6) social life function, (7) daily work function (mental), and (8) mental health. Furthermore, these subscales are divided into physical health, mental health, and work / social health for scoring. The higher the value, the better the health status.

[0111] In addition, the VAS can be used to evaluate the severity of the following five symptoms once a day from 7 days before the expected menstruation to the 4th day of menstruation: (1) lower abdominal pain, (2) rough skin, (3) edema, (4) irritability, and (5) depression.

[0112] In more detail, subjects who consciously have symptoms associated with menstruation are asked to take the test ingredients once a day to several times, and take several sexual cycles, such as 3 sexual cycles. Before taking the test ingredients, during the first menstruation after taking the test ingredients, during the second menstruation, etc., the evaluation items before menstruation (for example, 7 days before the expected arrival of menstruation to 1 day before the start of menstruation) and during menstruation (for example, from the first day of menstruation to the fourth day of menstruation) are investigated. When the result is that the improvement of at least one symptom is observed in the intake group, it can be evaluated that the ingredient is effective. The evaluation can be performed by comparing with the placebo intake group, and can also be performed by comparing with before intake.

[0113] The composition of the present embodiment is useful for treating any of premenstrual physical discomfort symptoms and premenstrual mental discomfort symptoms among the symptoms associated with menstruation, and is particularly useful for treating premenstrual mental discomfort symptoms.

[0114] Symptoms of mental discomfort specifically include impatience, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm. Impatience can be evaluated, for example, using VAS. Depression (low mood) can be evaluated, for example, using MDQ in the form of score changes of "excited mood". Intolerance and irritability can be evaluated, for example, using MDQ in the form of score changes of "feeling people are cute". Confusion and emotional instability can be evaluated, for example, using MDQ through score changes of "things are pleasing to the eye". Dissatisfaction can be evaluated, for example, using MDQ through score changes of "feeling happy". Despair, decreased vitality, fatigue and decreased enthusiasm can be evaluated by MDQ through score changes of "feeling energetic and positive".

[0115] Symptoms of physical discomfort include lower abdominal pain, rough skin, and edema.

[0116] In one embodiment, the composition is used to control the premenstrual mood. In the present invention, control includes upward control (increase, increase) and downward control (decrease, inhibit). In a particularly preferred embodiment, the composition is used to increase the premenstrual mood.

[0117] In another embodiment, the composition is used to control premenstrual irritability. In a particularly preferred embodiment, the composition is used to suppress premenstrual irritability.

[0118] The composition of this embodiment is expected to be useful in treating known diseases whose symptoms worsen with the menstrual cycle, including, for example, dysmenorrhea (functional, organic), depression, anxiety disorder, panic disorder, allergies, perimenopause, and the like.

[0119] In one embodiment, the composition of this embodiment can be used for non-disease treatment purposes for menstrual symptoms that are not diseases. Menstrual symptoms that are not diseases refer to conditions that do not affect daily life and do not require treatment by a doctor.

[0120] (Target)

[0121] The composition of this embodiment is suitable for administration to the following subjects: subjects who expect or need to deal with symptoms associated with menstruation; subjects who expect or need to deal with any of the symptoms of physical discomfort before menstruation and the symptoms of mental discomfort before menstruation; subjects who expect or need to deal with one or more selected from irritability, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm; subjects who are not troubled by menopausal symptoms; subjects in adolescence or sexual maturity; subjects who expect or need to control the excitement before menstruation; subjects who expect or need to control irritability before menstruation. Subjects who expect... include those who feel that they have such symptoms.

[0122] The subjects to whom the composition of the present embodiment is administered are different from subjects with menopausal symptoms. Women usually experience four physiological periods (puberty, sexual maturity, menopause, and old age) as they age. Although there are individual differences, they usually experience amenorrhea around the age of 50. The 10 years before and after the amenorrhea period (usually around 45 to 55 years old) are called "menopause", which can be divided into subjects in menopause and non-menopausal subjects (subjects in puberty or sexual maturity). In addition, the composition of the present embodiment can be administered to subjects who are not troubled by menopausal symptoms.

[0123] There is no particular age restriction on the subject, and the subject may be, for example, over 18 years old, over 25 years old, or under 45 years old, or under 40 years old.

[0124] The composition of this embodiment is particularly suitable for: women who feel physical or mental discomfort, especially mental discomfort, before menstruation, but do not need to see a doctor or affect their daily life, or do not want to be treated by a doctor; and healthy women who are over 25 years old and less than 40 years old, whose menstrual cycles in the past 6 years were within the range of 25 to 38 days, whose menstruation usually lasted for 3 to 7 days, and who feel certain menstrual symptoms before and during menstruation.

[0125] With respect to the present invention, healthy women refer to women who do not belong to the following: pregnant or breastfeeding women; those who have a history of or are currently suffering from gynecological diseases; those who are allergic to food; those who suffer from diarrhea after consuming dairy products; those who have the habit of taking analgesics prophylactically before the onset of menstrual pain; those who have severe menstrual symptoms that cannot be controlled by commercially available analgesics; those whose area is IV according to the Cornell Medical Index (CMI) health questionnaire·neurosis discrimination chart; those whose stress level score is 20 points or more according to the simple stress examination chart; and other persons who are deemed by doctors to be unsuitable for administration of the composition of this embodiment.

[0126] [Composition]

[0127] (Food composition, etc.)

[0128] The composition of the present embodiment can be set as a food composition or a pharmaceutical composition. Except for the cases of special records, food and medicine include not only food and medicine for people, but also food and medicine for animals other than people. Except for the cases of special records, food includes general food, functional food, nutritional composition, and also includes therapeutic food (food for therapeutic purposes. Food cooked based on a menu prepared by a doctor, a dietitian, etc. according to the recipe.), diet therapy food, formula food, nursing food, and treatment support food. Except for special records, food includes not only solids, but also liquid food, such as beverages, drinking agents, liquid food and soup. Functional food refers to food that can give a specified functionality to an organism, including, for example, specific health food (including special protection [specific health food] with additional conditions), functional labeled food, health functional food including nutritional functional food, special purpose food, nutritional supplement food, health supplement food, supplement (for example, tablets, coated tablets, sugar-coated tablets, capsules, liquid preparations and other various dosage forms of food), beauty food (for example, weight loss food) and other all health foods. In addition, the term "functional food" in the present invention includes health foods that apply health claims based on food standards of the Codex (FAO / WHO Joint Food Standards Commission). The composition may be a purified product of a specific sugar. The purified product includes a fractionated product, a partially purified product, and a crude purified product.

[0129] (Given by, etc.)

[0130] The composition of the present invention can be administered orally, parenterally, for example, via a tube (gastrostomy fistula, intestinal fistula), or nasally, preferably orally. In the present invention, administration is used to mean, in addition to administering a drug to a subject, causing a subject to ingest food other than a drug. Administration can also be replaced by ingestion, and in addition, administration can be replaced by administration.

[0131] The composition can be repeatedly administered to the subject, and can be administered to the subject continuously for a long period of time. The time is not particularly limited, and in order to make the effect fully visible, the administration can be continued for a long period of time, such as more than 3 days, more than 1 week, more than 2 weeks, more than 1 month, more than 3 months, more than 6 months, more than 1 year, or more than 1 sexual cycle, more than 2 sexual cycles, more than 3 sexual cycles, more than 4 sexual cycles, more than 5 sexual cycles, more than 6 sexual cycles.

[0132] The composition can be administered daily, or in advance or when necessary when the risk is high. The composition can be administered as a meal, before, after, or between meals, or when a disease or condition that is to be improved by the composition occurs.

[0133] (Dosage, content)

[0134] The dosage of the composition of the present embodiment may be any dosage that can produce the desired effect. The dosage may be appropriately set in consideration of various factors such as the age, weight, and symptoms of the subject.

[0135] The dosage of the composition per day can be set to 5 mg or more, 10 mg or more, preferably 50 mg or more, and more preferably 100 mg or more in terms of the amount of the active ingredient. The upper limit of the active ingredient per day can be set to 1000 mg or less, 900 mg or less, 700 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, or 200 mg or less at any lower limit. It should be noted that when a plurality of active ingredients are included in the composition, the amount of the active ingredient refers to the total amount of the active ingredients contained. Administration can be once a day, or it can be divided into multiple times a day, for example, 2 to 10 times.

[0136] The daily dosage of the composition can be set to 1×10 8 More than 2×10 8 More than 5×10 8 More than 1×10 9 More than 2×10 9 More than 5×10 9 More than 1×10 9 The upper limit of the effective ingredient per day can be set to 1×10 in terms of bacterial cell volume when the lower limit is any. 12 Less than 5×10 11 Less than 2×10 11 Less than 5×10 10 Less than 2×10 10 Less than .

[0137] The content of the active ingredient in the composition can be appropriately set according to the form of the composition. For example, when the composition is in the form of fermented milk or beverages that are directly eaten and drunk, the content of the active ingredient in each 100g composition can be set to 0.01% or more, can be set to 0.04% or more, preferably set to 0.1% or more, more preferably set to 0.2% or more, further preferably set to 0.5% or more, preferably set to 1% or more, preferably set to 10% or more, and preferably set to 15% or more. The upper limit of the active ingredient in each 100g composition can be set to 80% or less, 50% or less, 30% or less, or 20% or less in the case of any lower limit. Alternatively, the content of the active ingredient in each unit solid content of the composition can be set to 1% or more, more preferably 5% or more, further preferably 10% or more, and particularly preferably 15% or more. The upper limit of the active ingredient in each unit solid content can be set to 80% or less, 50% or less, 40% or less, or 20% or less in the case of any lower limit. In addition, regarding the present invention, % means mass % unless otherwise specified.

[0138] (Other ingredients, additives)

[0139] In the present invention, the composition may contain other active ingredients and nutrients that are permitted as food or medicine. Examples of such ingredients are lipids (e.g., milk fat, vegetable oils and fats, oils and fats containing medium-chain fatty acids), proteins (e.g., milk protein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg), heat-denatured whey protein, and enzyme-treated whey protein), amino acids (e.g., lysine, arginine, glycine, alanine, glutamic acid, leucine, isoleucine, valine), kojibiose, and koji Disaccharides include sugars other than oligosaccharides that constitute sugars (glucose, sucrose, fructose, maltose, trehalose, erythritol, maltitol, palatinose, xylitol, dextrin), electrolytes (e.g., sodium, potassium, calcium, magnesium), vitamins (e.g., vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, biotin, folic acid, pantothenic acid and niacin), minerals (e.g., copper, zinc, iron, cobalt, manganese), antibiotics, dietary fiber, etc.

[0140] In the present invention, the composition may contain prebiotics. Prebiotics refer to indigestible food ingredients that have a beneficial effect on the host and improve the health of the host by selectively changing the proliferation and activity of specific bacteria in the large intestine. In the composition, one or more prebiotics other than the active ingredient may be used.

[0141] Prebiotics are not particularly limited as long as they do not interfere with the effects of the active ingredients contained in the composition. Examples of prebiotics other than the active ingredients include galacto-oligosaccharides, fructo-oligosaccharides (GF2, GF3, GF4), xylo-oligosaccharides, isomaltooligosaccharides, raffinose, lactulose, lactofructooligosaccharides, soybean oligosaccharides, coffee oligosaccharides, dietary fiber, and gluconic acid.

[0142] In addition, the composition can also be used as a synbiotic, which can contain probiotics in addition to the active ingredients. Synbiotics refer to a combination of probiotics and prebiotics. Probiotics can refer to microorganisms that bring beneficial effects to the host by being introduced into the host's intestines in a living state.

[0143] There is no particular limitation on the probiotics as long as they do not hinder the effects of the active ingredients contained in the composition. As examples of probiotics, specific lactic acid bacteria and the like are known.

[0144] In addition, the composition may further comprise additives that are permitted as food or medicine. Examples of such additives are inactive carriers (solid carriers, liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, solubilizers, suspending agents, coating agents, colorants, preservatives, buffers, pH regulators, emulsifiers, stabilizers, sweeteners, antioxidants, spices, acidulants, and natural substances. More specifically, water, other aqueous solvents, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, water-soluble dextrin, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, vaseline, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, sucralose, stevioside, aspartame, acesulfame potassium, citric acid, lactic acid, malic acid, tartaric acid, phosphoric acid, acetic acid, fruit juice, vegetable juice, etc.

[0145] (Dosage form and form)

[0146] In one embodiment, the food composition can be made into any form such as solid, liquid, mixture, suspension, powder, granule, paste, jelly, gel, capsule, etc. In addition, the food composition of this embodiment can take any form such as dairy products, supplements (such as tablets, coatings, sugar-coated tablets, enteric treatment agents based on enteric coatings, etc., capsules (enteric soft capsules, enteric hard capsules, large intestine delivery capsules, etc.), snacks, beverages, drinking agents, seasonings, processed foods, side dishes, soups, etc. More specifically, the composition of this embodiment can take any form such as liquid food, semi-liquid food, jelly, gel, powder, formula milk powder, formula liquid milk, maternal milk powder, milk powder for lactating women, liquid milk, fermented milk, bar snacks, mousse, chocolate, biscuits, ice cream, fermented milk, lactic acid bacteria beverages, dairy beverages, milk beverages, refreshing beverages, fruit juice beverages, tableted foods, cheese, bread, biscuits, crackers, pizza crust, patient food, nutritional food, frozen food, processed food, etc. In addition, it can be made into the form of granules, powders, pastes, thick liquids, etc. for mixing with beverages and foods for administration. Granules and powders can be in the form of squares or sticks (formulated by packaging the amount for one time). In relation to the present invention, formula milk powder refers to: as defined in the provincial order on the composition standards of milk and dairy products (hereinafter referred to as the "milk, etc. provincial order"), raw milk, cow's milk, especially cow's milk or raw buffalo milk, or foods made from these as raw materials are processed or used as the main raw materials and nutrients required by infants and young children are added thereto and made into powder. In relation to the present invention, formula liquid milk refers to raw milk, cow's milk, especially cow's milk or raw buffalo milk, or foods made from these as raw materials are processed or used as the main raw materials and nutrients required by infants and young children are added thereto and are in liquid form.

[0147] In one embodiment, the pharmaceutical composition can be prepared into any dosage form suitable for oral administration, such as solid preparations such as tablets, granules, powders, pills, capsules, liquid preparations such as solutions, suspensions, syrups, gels, aerosols, etc.

[0148] (Manufacturing method, etc.)

[0149] In one embodiment, in the manufacture of the composition, the stage of the active ingredient can be appropriately selected. As long as the properties of the active ingredient are not significantly damaged, the stage of the active ingredient is not particularly limited. For example, the active ingredient can be mixed with the raw material for combination. Alternatively, the active ingredient can be added in the final stage of the manufacture to manufacture a composition containing the active ingredient.

[0150] (mark)

[0151] In one embodiment, the purpose of use (application) can be indicated for the composition. The labeling can be carried out in accordance with the domestic labeling-related laws and regulations for implementing the present invention. In one embodiment, the function brought by the composition or active ingredient and the method of use based on the function are indicated. Examples of methods of use based on the indicated functions are as described in relation to functions, actions, and effects. In addition, for the composition of this embodiment, it can be indicated that it can be used as a prebiotic or as a synbiotic (a composition of probiotics and prebiotics).

[0152] In one embodiment, the composition indicates that it is recommended to be administered to a specific subject. Examples of the indicated subject are as described above with respect to the subject.

[0153] Labeling can be explicit or implicit. Examples of explicit labeling include direct recording on the product itself, packaging, containers, signs, labels and other tangible objects. Examples of implicit labeling (also called implied) include advertising and promotional activities based on places or means such as web pages, stores, brochures, exhibitions, media seminars and other seminars, books, newspapers, magazines, television, radio, online video sharing platforms, SNS, mail, email, audio, etc.

[0154] In one embodiment, a labeling of a recommended composition for ingestion is performed on an individual. This labeling can be performed using a document (written or electronic) issued to the subject, a tablet terminal, a smartphone, a personal computer, or an SNS of the subject. In addition, this labeling can be performed together with the display of the results of any examination and analysis such as the subjective symptom examination of the subject.

[0155] [Example]

[0156] [manufacture]

[0157] The raw materials and proportions of the test foods and control foods evaluated below are shown in the following table. The powders uniformly mixed according to the following proportions were tableted using conventional methods.

[0158]

Table 1

[0159] Mixing ratio of 2 test food tablets

[0160]

[0161] *1The concentrated culture solution of Lactobacillus paragaseri OLL2809 was sterilized by heating at 85°C for 30 minutes.

[0162] *2 The culture medium used to cultivate the above lactic acid bacteria is freeze-dried and manufactured using common food raw materials containing milk components.

[0163] [evaluate]

[0164] 1. Methods

[0165] 1-1. Experimental design and experimental implementation system

[0166] This trial was commissioned by the Institute of General Medical Sciences, Inc. and was conducted in compliance with the ethical principles based on the Declaration of Helsinki and the ethical guidelines for human medical research (Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare of Japan, partially revised on February 28, 2017). This trial was approved by the Meiji Clinical Trial Review Committee (review number: SHEN-202) and the Ethics Committee of the Koshokai Fukuda Internal Medicine Clinic (review number: IRB-20210619-3) and was conducted at the Koshokai Fukuda Internal Medicine Clinic from May 2021 to September 2022. The trial plan was registered with the UMIN Clinical Trial Registry (UMIN-CTR) (trial ID: UMIN000044933) and was implemented with the consent of all subjects.

[0167] 1-2. Criteria for selection and exclusion of subjects

[0168] [Selection criteria]

[0169] Healthy adult females aged 25 years and above and below 40 years at the time of consent

[0170] Those whose past six menstrual cycles were within the range of 25 to 38 days and whose normal menstrual cycles lasted 3 to 7 days

[0171] Those who feel certain menstrual symptoms before and during menstruation

[0172] · The purpose and content of this trial have been fully explained to the patient, the patient has the ability to consent, and the patient has voluntarily signed up and agreed in writing to participate after fully understanding the trial.

[0173] 〔Exclusion criteria〕

[0174] · Pregnant, breastfeeding or potentially pregnant

[0175] ·People who have or are currently suffering from gynecological diseases

[0176] People with food allergies

[0177] People who have diarrhea from consuming dairy products

[0178] Drugs that may affect this trial from 2 months before consent was obtained to the date of consent (including traditional Chinese medicine and oral contraceptives)

[0179] Regular use of supplements

[0180] ・Those who consume foods that may affect the test results (foods and drinks containing lactic acid bacteria such as yogurt) more than 4 days a week

[0181] · Participated in other drug or food clinical trials from 1 month before consent was obtained to the date consent was obtained

[0182] ·People who have the habit of taking analgesics before menstrual pain occurs

[0183] · Those whose MDQ score after menstruation is 1 point higher than the MDQ score before menstruation and during menstruation in the Menstual Distress Questionaire (MDQ) (Non-Patent Document 4) during the initial screening

[0184] · Those whose symptoms are severe and cannot be controlled by commercially available analgesics

[0185] ·According to the Cornell Medical Index (CMI) health questionnaire ·Those with neurosis discrimination chart area IV

[0186] ·Those who have a stress level score of 20 or above according to the simple stress checklist

[0187] · Other people who the doctor in charge of the trial considers unsuitable as subjects of this trial

[0188] The subjects were instructed not to diet or overeat beyond normal limits during the trial period. In addition, they were instructed not to take analgesics for prevention purposes. In addition, the following explanation was made: In order to distinguish between temporary menstrual symptoms in healthy women and chronic discomfort caused by gynecological diseases, if the discomfort before or during menstruation interfered with daily life, or if the discomfort lasted not only before or during menstruation but also after menstruation, the subjects should go to a medical institution for treatment in a timely manner.

[0189] 1-3. Test food

[0190] The OLL2809 heating bacteria, which is a relevant component of this test, was produced at the Meiji Tokyo Lactobacillus Factory, the freeze-dried powder was produced at the Meiji Innovation Center, and the tableting and packaging were carried out at the API Co., Ltd. Ikeda Factory (Ibi-gun, Gifu Prefecture, Japan).

[0191] Test food: Each 2 capsules contain 100 mg (based on the number of bacteria, 1×10 10 OLL2809 heated bacteria tablet candy

[0192] Control food: Tablet candies containing the above active ingredients replaced with freeze-dried powder of OLL2809 culture medium and dextrin

[0193] 1-4. Test implementation steps

[0194] The subjects who obtained informed consent were subjected to blood sampling, urine sampling, physical examination, living situation questionnaire, CMI health questionnaire (Non-Patent Document 5), simple stress checklist (Katsura / Murakami version) (Non-Patent Document 6), MDQ and medical interview as the initial screening. From the subjects who met the selection criteria and did not conflict with the exclusion criteria, 120 subjects with high MDQ comprehensive scores in the initial screening were selected.

[0195] In the first sexual cycle, from 7 days before the expected menstruation to the 4th day of menstruation, (1) lower abdominal pain, (2) rough skin, (3) edema, (4) irritability, and (5) depression were evaluated using a visual analog scale (VAS). Figure 1 On the first and fourth days of menstruation, the Medical Outcomes Study 36-Item Short Form Health Survey v2 Acute Version (SF-36v2) (Non-Patent Document 7) and MDQ were administered. On the first day of menstruation, the subjects were asked about the perceived physical and mental changes from 7 days before the start of menstruation to the day before the start of menstruation, and on the fourth day of menstruation, the subjects were asked about the perceived physical and mental changes from the first day of menstruation to the fourth day of menstruation ( Figure 1 ). From the subjects who met the selection criteria and did not conflict with the exclusion criteria, 80 subjects whose MDQ comprehensive scores were close to the median in the secondary screening were selected and divided into 2 groups.

[0196] The subjects were asked to take the test food once a day from the 5th day of the menstruation in the 0th cycle to the 4th day of the menstruation in the 3rd cycle. In the 2nd and 3rd cycles, the VAS, SF-36 and MDQ ( Figure 1 ).

[0197] Please record the intake of test foods, subjective symptoms of physical changes, treatments received, drugs used, and health foods used from the start date of the second screening to the end date of the test in your life diary. The analgesic use score and test food intake rate are calculated based on the records in the life diary. Regarding the analgesic use score, "no analgesic use" is recorded as 0 points, "used once" is recorded as 1 point, "used twice" is recorded as 2 points, and "used more than 3 times" is recorded as 3 points. The values ​​of the 7 days from 7 days before menstruation to the day before menstruation are regarded as the values ​​of "before menstruation", and the values ​​of the 4 days from the 1st day to the 4th day of menstruation are regarded as the values ​​of "during menstruation".

[0198] 1-5. Evaluation items

[0199] The main evaluation item for the effectiveness evaluation of this trial was the MDQ score, and the secondary evaluation items were the VAS and SF-36 scores. The safety evaluation items were the presence or absence of adverse events and side effects.

[0200] MDQ: The MDQ was used to investigate the effect of OLL2809 on premenstrual and menstrual symptoms. The MDQ is a 46-item self-report questionnaire used to evaluate and treat premenstrual and menstrual symptoms. The 46 items are divided into the following 8 sub-factors: (1) pain, (2) water retention, (3) changes in the autonomic nervous system, (4) negative emotions, (5) decreased concentration, (6) behavioral changes, (7) euphoria, and (8) control. Among these sub-factors, only (7) euphoria was considered a positive change.

[0201] For the answers to each symptom, "none" was set to 0 points, "a little bit" was set to 1 point, "slightly strong" was set to 2 points, "strong" was set to 3 points, and "very strong" was set to 4 points. The sub-factor items were added together to obtain the sub-factor score. The scores of (1) pain, (2) water retention, (3) changes in the autonomic nervous system, and (8) control were added together to obtain the "physical symptom score." The scores of (4) negative emotions, (5) decreased concentration, and (6) behavioral changes were added together, and the score of (7) hyperactivity was subtracted to obtain the "mental symptom score." The mental symptom score and the physical symptom score were added together to obtain the overall score.

[0202] SF-36: SF-36 is used to evaluate health-related QOL. The answer sheet is processed according to the web scoring program of Qualitest Co., Ltd., and the eight subscales (1) physical function, (2) daily work function (physical), (3) body pain, (4) overall health, (5) vitality, (6) social life function, (7) daily work function (mental), and (8) mental health are scored within a range of 0 to 100. In addition, these subscales are divided into physical health, mental health, and work / social health for scoring. The higher the value, the better the health status.

[0203] VAS: Subjects were asked to record the severity of the following five symptoms once a day on a 100mm scale from 0 (no symptoms) to 100 (worst symptom ever experienced) from 7 days before the expected menstruation to the 4th day of menstruation: (1) lower abdominal pain, (2) rough skin, (3) edema, (4) irritability, and (5) depression. The maximum value of the seven days from 7 days before menstruation to the day before menstruation was taken as the value of "before menstruation", and the maximum value of the four days from the 1st day to the 4th day of menstruation was taken as the value of "during menstruation". However, since the start date of VAS responses is the prediction date, the survey period may change, so if the survey period before menstruation is less than 3 days, it will be recorded as missing.

[0204] 1-6. Target number of subjects

[0205] In a trial conducted in the past on patients with endometriosis (Non-Patent Document 2), the mean ± standard deviation of the change in menstrual pain VAS in the active agent group (n = 29) from the start of ingestion to 12 weeks after ingestion was -3.28 ± 1.94, which was significantly improved compared to -2.00 ± 1.67 in the placebo group (n = 33) (P < 0.01). The effect size (Hedges' g) of OLL2809 on menstrual pain VAS in this trial was 0.71. Based on this result, assuming that the effect size of OLL2809 on MDQ score in this trial is 0.7, the number of subjects per group is 33 at a significance level of 5% and a test power of 80%, so the required number of subjects is calculated to be 66. Considering the number of cases excluded from the effectiveness analysis and the dropout rate of about 10%, the target number of subjects is set to 80.

[0206] 1-7. Randomization

[0207] The person in charge of allocation was a person who had no direct relationship with the field staff and the subjects. The subjects with similar menstrual periods were divided into 5 groups. Each group was randomly allocated to two groups based on age, pre-menstrual MDQ comprehensive score before intake, and mid-menstrual MDQ comprehensive score, namely the test food intake group and the control food intake group.

[0208] 1-8. Blind inspection

[0209] The Ethics Review Committee of the medical corporation Koshokai Fukuda Internal Medicine Clinic conducted an unidentifiability test on the test food and confirmed that the test food and control food were unidentifiable.

[0210] The person in charge of distribution shall seal the distribution sheet and the correspondence sheet of test food identification codes immediately after distribution and strictly keep them until they are opened to maintain the blindness of this test for all relevant personnel except the person in charge of distribution.

[0211] 1-9. Statistical analysis

[0212] Data are presented as mean and standard deviation (SD) or standard error (SE). SPSS version 26 (IBM) was used for statistical analysis. Two-sided tests were used for all tests, and the significance level was 5%. In the comparison between groups of subject background, independent 2-sample t-test or Mann-Whitney U test was used for measurement data, and Fisher's exact probability test or Pearson χ test was used for count data. 2Test. In the evaluation of effectiveness, a multivariate regression analysis with the change from before intake to the third sexual cycle as the target variable was used. The group (placebo group = 0, OLL2809 group = 1), the score of analgesic use before intake, the stress level score, and the habit of regular exercise more than once a week (no = 0, yes = 1) were used as explanatory variables. In this trial, there was a significant difference in the score of analgesic use between the two groups, and in previous studies, stress and exercise habits may affect menstrual symptoms (non-patent literature 3, 8), so these were used as explanatory variables. The variance inflation factor (VIF) of these explanatory variables was less than 10, and there was no multicollinearity problem between the explanatory variables. The adjusted estimates of the inter-group differences are expressed with 95% confidence intervals (CI). In other analyses, the t-test of two independent samples was used for the inter-group comparison, and the corresponding t-test was used for the comparison before and after intake.

[0213] 2. Results

[0214] 2-1. Subject selection

[0215] 207 people agreed to participate in the trial. Because 9 people dropped out for their own reasons, 198 people were screened once. 120 people entered the secondary screening, and 80 were included in this trial, divided into two groups, 40 in each group. One person in the OLL2809 group (for health reasons unrelated to this trial) and two people in the placebo group (one person was judged to be unqualified after the start of the trial because he started taking drugs that may affect this trial, and one person seriously did not comply with the trial implementation plan) were judged by the doctor in charge of the trial that the trial should be terminated. Therefore, the analysis subjects of the effectiveness evaluation were 39 people in the OLL2809 group and 38 people in the placebo group ( Figure 2 ). No cases were excluded from the analysis due to deviations from the trial implementation plan.

[0216] There were no significant differences in the background characteristics between the OLL2809 group and the placebo group in terms of age, BMI, age at menarche, menstrual cycle, menstrual period, daily alcohol intake, simple stress level score, MDQ score before / during / after menstruation, neurosis discrimination map area based on the CMI health questionnaire, smoking, regular exercise habits more than once a week, and premenstrual analgesic use score (Table 1). Compared with the OLL2809 group, the placebo group had a significantly higher score for analgesic use during menstruation.

[0217] The mean values ​​of the test food intake rates were 97.8% in the OLL2809 group and 98.3% in the placebo group, with no significant difference between the groups.

[0218]

Table 2

[0219] Table 1 Background of the subjects of effectiveness analysis

[0220]

[0221] Data are shown as mean ± SD or number (percentage). a Student's t test. b Chi-square test. c Fisher's exact test. d Mann-Whitney U test.

[0222] Abbreviations: MDQ, menstrual symptoms questionnaire; J-CMI, Cornell Medical Index health questionnaire

[0223] 2-2. Effect of OLL2809 on premenstrual symptoms

[0224] The MDQ scores before menstruation are shown in Table 2. Among the MDQ sub-factors, the change in the "arousal" score of the OLL2809 group after three sexual cycles was significantly higher than that of the placebo group ( Figure 3 Further analysis of the symptoms affecting the "excited mood" factor revealed that the "bursts of energy, activity" item was significantly higher in the OLL2809 group compared with the placebo group ( Figure 4 ). Regarding the items of "feeling that people are cute (Affectionate)", "feeling that things are pleasing to the eye (Orderliness)", "feeling excited (Excitement)", and "feelings of well-being (Feelings of well-being)", no significant differences were found between the groups, but the OLL2809 group showed higher values.

[0225] The results of SF-36 and VAS before menstruation are shown in Table 3. In the VAS-based evaluation of "Irritabily", the change in the OLL2809 group after three sexual cycles of intervention was significantly lower than that in the placebo group ( Figure 5 Regarding "depression", the change in the OLL2809 group after 3 sexual cycles showed a downward trend compared with the placebo group (P = 0.070).

[0226]

Table 3

[0227] Table 2 Estimated differences in premenstrual MDQ scores and changes between groups

[0228]

[0229] Data are shown as mean ± SE (n = 38 in the placebo group, n = 39 in the OLL2809 group). Compared with the baseline, paired t test, * p<0.05, multiple regression analysis.

[0230]

Table 4

[0231] Table 3 Estimated differences between groups in changes in premenstrual SF-36 and VAS scores

[0232]

[0233] Data are shown as mean ± SE (n = 38 in the placebo group, n = 39 in the OLL2809 group). Compared with the baseline, paired t test, * p<0.05, multiple regression analysis.

[0234] Abbreviations: PCS, physical factors summary; MCS, mental factors summary; RCS, role / social factors summary.

[0235] 2-3. Effect of OLL2809 on menstrual symptoms

[0236] Regarding the MDQ scores during menstruation, there were no significant differences between the groups in the comprehensive score, physical symptom score, and mental symptom score. In addition, there were no significant differences between the groups in the MDQ sub-factors. Regarding the VAS scores during menstruation and SF-36, there were no significant differences between the groups in any of the items.

[0237] 2-4. Safety evaluation of OLL2809

[0238] In this trial, adverse events were defined as new bad or unexpected injuries or diseases or their signs that occurred from the start of the test food intake to the end of the trial. No serious adverse events were found in this trial. During the adverse event observation period (day 5 of menstruation in the 0th cycle to day 4 of menstruation in the 3rd cycle), there were 34 new adverse events in the OLL2809 group and 34 in the placebo group, and there was no difference in the incidence between the two groups. The adverse events found all had clear causes and were considered to be temporary or sporadic, so it was judged that they were not related to the intake of the test food.

[0239] 3. Investigation

[0240] Among Japanese women, the use of analgesics is the most common method of treating pain associated with menstruation. This trial excluded those who had the habit of taking analgesics prophylactically before the onset of dysmenorrhea, and instructed the subjects not to take analgesics prophylactically before the onset of symptoms, so as to avoid the use of analgesics affecting the evaluation of symptoms associated with menstruation as much as possible during the implementation of the trial. However, from the perspective of protecting the subjects, there was no restriction on taking analgesics when symptoms appeared. Therefore, it was expected that the use of analgesics would be a large confounding factor, and in fact, significant between-group differences were found in the analgesic use scores during the pre-intake period (Table 1). Therefore, together with other factors affecting symptoms associated with menstruation, multiple regression analysis with the analgesic use score as an explanatory variable was performed. The results showed that in the 3 pre-menstrual MDQ "excited mood" factor after the sexual cycle intervention, which was the main evaluation item, the OLL2809 group showed significantly higher scores than the placebo group. In particular, the study showed that the intake of OLL2809 significantly improved the decline in pre-menstrual vitality. In addition, in the VAS-based evaluation of the secondary evaluation item "irritability", the premenstrual score in the OLL2809 group was significantly reduced compared with the placebo group. These results suggest that taking OLL2809 can reduce the decrease in premenstrual vitality and irritability and improve menstrual symptoms.

[0241] In this study, the effect of OLL2809 on improving premenstrual mental symptoms was obtained. On the other hand, no improvement effect was found under experimental conditions for premenstrual physical symptoms and symptoms during menstruation. There are many reports on the association between physical symptoms and mental symptoms associated with menstruation, such as headaches and migraines caused by neurovascular diseases caused by premenstrual estrogen release and lower abdominal pain caused by uterine contraction caused by prostaglandins, which are said to affect mental symptoms such as depression and impatience (non-patent literature 10). In a report verifying the association between physical symptoms of the menstrual cycle and premenstrual depressive symptoms, when physical symptom scores were used as predictors of depressive symptoms, strong linear effects and moderate curvilinear effects were observed. When the level of physical symptoms was low, no correlation between physical symptoms and depressive symptoms was observed, but as the level of physical symptoms increased, the correlation became stronger (non-patent literature 9). The effect of OLL2809 on improving symptoms associated with menstruation is exerted before menstruation when the level of physical symptoms is relatively low. In menstruation where the symptoms of menstrual pain (lower abdominal pain, headache) are stronger than before menstruation, it may have no effect on physical symptoms and mental symptoms affected by physical symptoms.

[0242] 4. Conclusion

[0243] This study was conducted as a randomized, placebo-controlled, double-blind, parallel-group comparative study with healthy women who felt they had symptoms associated with menstruation as subjects, and OLL2809 as the test food. Since the subjects were healthy adult women, subjects with diseases such as PMS, PMDD, dysmenorrhea, or endometriosis and subjects who were judged to have neurosis were excluded. In addition, subjects whose symptoms were so severe that they affected their daily lives were also excluded due to the presence of the above-mentioned disease background. Therefore, the results of this study can be considered meaningful because it can provide a treatment method other than drugs for women who feel mental discomfort before menstruation but do not need to go to the hospital. In summary, it was confirmed that continuous intake of OLL2809 for 3 sexual cycles in healthy women can improve premenstrual vitality decline and irritability, indicating that OLL2809 can help improve women's QOL.

[0244] 5. References cited in the specification

[0245] (Non-patent document 2) Itoh H, Uchida M, Sashihara T, et al. Lactobacillus gasseriOLL2809 is effective especially on the menstrual pain and dysmenorrhea inendometriosis patients: randomized, double-blind, placebo-controlled study. Cytotechnology 2011:63:153-161.

[0246] (Non-patent document 3) Matsumoto T, Egawa M, Kimura T, Hayashi TA potentialrelation between premenstrual symptoms and subjective perception of health and stress among college students: a cross-sectional study. BioPsychoSocialMedicine2019:13:26.

[0247] (Non-patent document 4) Moos RH. The development of a menstrual distress questionnaire. Psychosom Med 1968: 30: 853-867.

[0248] (Non-private reference 5) Ken Fukamachi. Study on the Cornell Medical Index (Part 2) Criteria for distinguishing neurotic patients using the CMI. Fukuoka Medical Journal 1959:50:3001-3009.

[0249] (Non-private reference 6) Masato Murakami. Research on the stress state of healthy people, how symptoms caused by stress appear and how to deal with them. Psychosomatic Medicine 1989:1:72-82.

[0250] (Non-profit reference 7) Fukuhara S, Bito S, Green J, Hsiao A, Kurokawa K. Translation, adaptation, and validation of the SF-36 Health Survey for use inJapan.J Clin Epidemiol 1998:51:1037-1044.

[0251] (Reference 8) Mizuta R, Maeda N, Komiya M, et al.The relationship between the severity of perimenstrual symptoms and a regular exercise habit inJapanese young women:a cross-sectional online survey.BMC Womens Health2022:22:200.

[0252] (Reference 9)Kiesner J.Physical characteristics of the menstrual cycle and premenstrual depressive symptoms.Psychol Sci 2009:20:763-770.

[0253] (Non-profit reference 10) Kiesner J, Eisenlohr-Moul T, Mendle J. Evolution, the Menstrual Cycle, and Theoretical Overreach. Perspect Psychol Sci 2020:15:1113-1130.

[0254] Industrial availability

[0255] The present invention helps maintain and improve human health by using a composition for treating menstrual symptoms containing lactic acid bacteria belonging to Lactobacillus paragaseri. In addition, according to the present invention, a food composition and a method for producing a food that help maintain and improve human health can be provided. Furthermore, the present invention can achieve nutritional improvement for various groups of people, ensure healthy living, and promote well-being.

[0256] [Sequences listed in the sequence listing]

[0257] Sequence number 1: Lactobacillus paragaseri OLL2809 16s rRNA gene.

Claims

1. Use of a composition comprising lactic acid bacteria belonging to Lactobacillus paragasseri for non-disease therapeutic purposes of treating symptoms associated with menstruation.

2. The use according to claim 1, wherein Symptoms associated with menstruation are any of symptoms of physical discomfort before menstruation and symptoms of mental discomfort before menstruation.

3. The use according to claim 1, wherein Menstrual associated symptoms are symptoms of mental discomfort before menstruation.

4. The use according to claim 1, which is for ingestion by a subject who is not suffering from menopausal symptoms or a subject in adolescence or sexual maturity.

5. The use according to claim 1, wherein The symptoms associated with menstruation are symptoms of mental discomfort, and the symptoms of mental discomfort are one or more selected from irritability, depression (low mood), intolerance, irritability, confusion, emotional instability, dissatisfaction, despair, decreased vitality, fatigue and decreased enthusiasm.

6. Use of a composition comprising Lactobacillus paragaseri for non-disease therapeutic purposes for controlling premenstrual euphoria.

7. Use of a composition comprising Lactobacillus paragaseri for the non-disease therapeutic purpose of controlling premenstrual irritability.

8. The use according to any one of claims 1 to 7, wherein The composition contains Lactobacillus paragaseri in the form of heated cells.

9. The use according to any one of claims 1 to 7, wherein The composition contains only the bacterial cells of Lactobacillus paragaseri as an effective ingredient.

10. The use according to any one of claims 1 to 7, wherein Lactobacillus paragaseri is Lactobacillus paragaseri OLL2809 deposited under the accession number NITE BP-72 or a strain taxonomically equivalent thereto.

11. The use according to any one of claims 1 to 7, wherein The composition is for a daily intake of 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

12. Use for the non-disease therapeutic purpose of treating symptoms associated with menstruation, comprising the step of causing a subject to ingest a composition containing lactic acid bacteria belonging to Lactobacillus paragaseri.

13. The use according to claim 12, wherein As a daily intake, take 1×10 8 ~1×10 12 A cell of Lactobacillus paragaseri.

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