TWI309983B

TWI309983B - Medicine for inhibiting climacteric symptom

Info

Publication number: TWI309983B
Application number: TW93134486A
Authority: TW
Inventors: Masaji Matsunaga; Shunji Saito
Original assignee: Nissan Chemical Ind Ltd; Nissei Bio Co Ltd
Priority date: 2004-11-11
Filing date: 2004-11-11
Publication date: 2009-05-21
Also published as: TW200614998A

Description

1309983 (1) 九、發明說明【發明所屬之技術領域】本發明係關於由攝取而可有效地抑制更年期中之各種 - 不舒適症狀，亦即更年期障礙之更年期障礙抑制劑以及含 __ 該有效量之健康食品者。. t 【先前技術】由壯年期至老年期間，隨著年齡的增加而伴隨著身體 Φ 的老化，不僅人的外觀變化（肌力降低、肥滿、脫毛、斑點或皴紋增加等）或精神力降低，多伴隨有內分泌系統之功能降低或異常。激素例如女性激素（雌性激素或黃體激素）的減少，帶來女性所謂的更年期障礙。不僅女性，最近，起因自男性激素（睪九激素）減少之男性更年期障礙亦成爲問題。更年期障礙，尤其對於女性有深刻的問題，誘發如下所示之各種症狀。 · (a )月經異常月經週期的縮短或延長、月經次數減少及不正常出血等。 (b )血管反應系統的變化熱潮紅或血氣上衝等之突然發生的發熱感。 -5- (2) 1309983 (c )精神症狀失眠或憂鬱症狀等。 (d )泌尿生殖器症狀頻尿或尿失禁等。 (e)其他骨質疏鬆症、高脂血症及動脈硬化等。，可舉例如易缺乏之女液或貼附劑法。其他，如亦嘗試由 )以抑制更及特開2003 之食品，可作爲女性之更年期障礙之代表性治療方法激素補充療法。激素補充療法係更年期女性容性激素（雌性激素或黃體激素），由使用內服型態之製劑補充，治療或抑制更年期障礙之方亦可使用例如漢方療法。除了如激素補充療法或漢方療法以外，例每曰攝取含特定成份之食品（所謂的健康食品年期障礙（參考例如特開2〇〇 1 - 069946號公報 - 1 1 3 1 1 7號公報）。有效地抑制更年期障礙用舉例如含異黃酮或骨質蛋白質之食品。專利文獻1 :特開200 1 - 069946號公報專利文獻2 :特開2〇〇3 - 1 I3 1 I7號公報【發明內容】發明之揭示發明所欲解決之課題 -6- (3) 1309983 上述之激素補充療法係有治療或抑制更年期障礙之效果，相反地，亦有產生各種副作用的危險（例如增大乳癌或子宮癌等之發病率等）。另外，激素補充療法或漢方療法係必須基於專業醫師的指示，嚴格地進行，稱不上爲簡便的方法。傳統上，即使對於抑制更年期障礙具有效果之食品（或添加於食品之特定成份），對於更年期障礙之全體多種症狀（症候群），當然並未顯示效果受到具體地實際證實之有效性。因此，強烈希望任何人都可簡便地且安全地實施更年期障礙之抑制手段。本發明係爲解決上述傳統技術之問題點者，作爲該目的係提供可經口地且容易地攝取，由規則地（例如每曰）攝取’可有效地抑制更年期障礙之更年期障礙抑制劑及含該有效量之健康食品。課題之解決手段本發明者等努力硏究關於抑制更年期障礙之結果，發現核精蛋白（nucleoprotamine )係可有效地抑制更年期障礙而完成本發明。本發明之更年期障礙抑制劑係以含核精蛋白爲有效成份爲特徵。上述核精蛋白係可使用得自魚類精巢之核精蛋白。上述魚類可爲鮭魚、鱒魚、緋魚或鳕魚。 (4) (4)1309983 本發明之健康食品係以含有效量之本更年期障礙抑制劑爲特徵。發明之功效本發明之更年期障礙抑制劑係可容易地經口攝取，亦無副作用，由適量地攝取，可有效地抑制大範圍的更年期障礙。另外’本發明之健康食品係含有效量之本更年期障礙抑制劑’可爲固體、液體、透明凍膠狀及糊狀等之各種型態’因爲可適當地選擇最適合之型態，所以適合每日攝取用以實施發明之最佳型態本發明之更年期障礙抑制劑之有效成份之核精蛋白係存在於脊椎動物之成熟精核中之鹼性蛋白質之魚精蛋白與核酸鍵結所成之複合體者，形成精子之染色質。魚精蛋白係分子量小（通常分子量爲1萬以下），構成胺基酸之大部份係鹼性胺基酸，尤其爲精胺酸，來自精胺酸之氮係相當於總含氮量之2 5至9 0 %，通常不含酸性胺基酸。精胺酸係具有多種生理作用，有鎭靜效果、刺激內分泌效果及保護消化道功能之效果等。核精蛋白係多含於魚類，例如鮭魚、鱒魚、鲱魚或鳕魚之精巢中，例如可以將魚類之精巢除去皮、筋及血管等 -8- (5) 1309983 之後，以乾燥或萃取等之常用方法精製而製狀、顆粒狀、糊狀及液狀等之各種型態。由攝取核精蛋白，可同時攝取魚精蛋白核酸中有去氧核糖核酸（DNA )與核糖，保存生物之遺傳訊息。魚類精巢中係含有呤（A )、胸腺嘧啶（T )、鳥糞嘌呤（G ). )之四種核酸爲組成要素所成之DNA。核酸細胞，防止老化之效果。本發明之更年期障礙抑制劑之使用型態限制，例如粉末、顆粒、錠劑、膠囊劑、透之各種型態之健康食品（含健康飮料）等。爲例如水溶液、懸濁液等。可直接使用核精明之更年期障礙抑制劑，因應所需，亦可適的有效成份（例如維生素類等）。本發明之更年期障礙抑制劑中之核精蛋本發明之健康食品中之本更年期障礙抑制劑應需要而可適當地選擇。本發明之健康食品係本更年期障礙抑制含添加於通常食品所得者。本發明之更年期障礙抑制劑係適合每曰日攝取如0.1至10g，以0.2至5g之量爲宜。本期障礙抑制劑係可每日分1至3次攝取，但依更年期障礙之症狀等而適當地增減攝取量。造，可爲粉末及核酸。核酸（RNA) 大量的以腺嘌及胞嘧啶（C 係具有活化，並無特別的明凍膠、漿糊健康飮料係可蛋白作爲本發量地添加其他白之含有率或之含有率係因劑以外，亦包，例如相當每 :發明之更年年齡、體重及 (6) (6)1309983 【實施方式】實施例由下述之實施例更詳細地說明本發明。 (1 )製造本發明之更年期障礙抑制劑以下述步驟’由鮭魚精巢製造本發明之更年期障礙抑制劑。 i :鮭魚精巢之前處理取1 0 0 0 g之鮭魚精巢，進行去血及水洗。瀝水後，加入3 0 0ml的水，磨碎、攪拌而得懸濁液。 I i :粉末化處理過濾上述懸濁液，除去精巢的皮等之固形物後，以噴霧乾燥器噴霧乾燥而得粉末狀物質。1309983 (1) IX. INSTRUCTIONS OF THE INVENTION [Technical Field] The present invention relates to an inhibitor of menopausal disorder which is effective in suppressing various types of discomfort during menopause, that is, menopausal disorders, and __ A quantity of healthy food. t [Previous technique] From the aging to the old age, with the increase of age, accompanied by the aging of the body Φ, not only the change in appearance of the human body (reduced muscle strength, plump, hair removal, increase of spots or crepe lines, etc.) or spirit The force is reduced, and the function of the endocrine system is often reduced or abnormal. The reduction of hormones such as female hormones (estrogen or lutein) leads to so-called menopausal disorders in women. Not only women, but also male menopausal disorders, which are caused by a decrease in male hormones (睪九激素), have become a problem. Menopausal disorders, especially for women, have profound problems that trigger the symptoms shown below. · (a) Abnormal menstruation The shortening or prolongation of the menstrual cycle, the reduction in the number of menstrual cycles, and abnormal bleeding. (b) Changes in the vascular response system The sudden onset of fever such as hot flashes or blood gas rushing. -5- (2) 1309983 (c) Psychiatric symptoms Insomnia or depression symptoms. (d) genitourinary symptoms, frequent urination or urinary incontinence. (e) Other osteoporosis, hyperlipidemia, and arteriosclerosis. For example, it is easy to lack a female liquid or a patching method. Others, such as try to inhibit the food of the special 2003, can be used as a representative treatment for menopausal disorders in women. Hormone supplement therapy. Hormone-supplementation therapy is a menopausal female hormone (estrogen or luteinizing hormone) that is supplemented with a formulation that uses internal medicine to treat or inhibit menopausal disorders. For example, Hanfang therapy can also be used. In addition to, for example, hormone supplementation therapy or Hanfang therapy, foods containing specific ingredients are taken every time (the so-called health food age disorder) (refer to Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. 2-069946 - 1 1 3 1 1 7 ) For the purpose of effectively suppressing menopausal disorders, for example, foods containing isoflavones or bone protein are disclosed. Patent Document 1: JP-A No. 2001-069946 Patent Document 2: JP-A-2-31-I1 1 I7 】 Disclosure of the Invention Problems to be Solved by the Invention-6- (3) 1309983 The above-mentioned hormone supplementation therapy has the effect of treating or inhibiting menopausal disorders, and conversely, it also has the risk of causing various side effects (for example, increasing breast cancer or uterine cancer) In addition, hormonal supplementation therapy or Hanfang therapy must be carried out strictly according to the instructions of a professional physician, and it is not a simple method. Traditionally, even foods that are effective in inhibiting menopausal disorders (or addition) For the specific ingredients of food, for the various symptoms (symptoms) of menopausal disorders, of course, the effect has not been shown to be specifically verified. Therefore, it is strongly desired that any person can easily and safely implement the means for suppressing menopausal disorders. The present invention is to solve the problems of the above conventional techniques, and as such a purpose, it is possible to provide oral and easy ingestion. In order to prevent the menopausal disorder, the inventors of the present invention have tried to infect the menopausal disorder which is effective in suppressing menopausal disorders, and the health food containing the effective amount. The nucleoprotamine system can effectively inhibit menopausal disorders and complete the present invention. The climacteric inhibitor of the present invention is characterized by containing nuclear fibrin as an active ingredient. The above nuclear protamine can be obtained from a fish testis core. The above-mentioned fish may be squid, squid, squid or squid. (4) (4) 1309983 The health food of the present invention is characterized by containing an effective amount of this climacteric disorder inhibitor. The climacteric disorder inhibitor can be easily orally ingested, has no side effects, and is ingested in an appropriate amount, which is effective A wide range of menopausal disorders. In addition, the health food of the present invention contains an effective amount of the present menopausal disorder inhibitor, which can be various types of solid, liquid, transparent jelly, and paste, etc. It is suitable for daily intake of the best form of the invention. The nuclear protamine of the active ingredient of the menopausal inhibitor of the present invention is a basic protein of fish that is present in the mature sperm nuclei of vertebrates. The complex of protein and nucleic acid bonds forms the chromatin of sperm. The protamine protein has a small molecular weight (usually a molecular weight of 10,000 or less), and most of the amino acids are basic amino acids, especially Arginine, a nitrogen system derived from arginine, corresponds to 25 to 90% of the total nitrogen content and is usually free of acidic amino acids. The arginine has a variety of physiological effects, such as a calming effect, an stimulating endocrine effect, and an effect of protecting the function of the digestive tract. The nuclear protamine is mostly contained in fish, such as the testis of squid, squid, squid or squid. For example, the testis of fish can be removed from the skin, tendons and blood vessels, etc. -8- (5) 1309983, followed by drying or extraction. The conventional methods are refined in various forms such as a form, a granule, a paste, and a liquid. By ingesting nuclear protamine, it is possible to simultaneously take protamine. The nucleic acid contains deoxyribonucleic acid (DNA) and ribose, and preserves the genetic information of the organism. The fish testis contains four kinds of nucleic acids: 呤 (A), thymine (T), and guano (G). Nucleic acid cells prevent the effects of aging. The use form of the menopausal disorder inhibitor of the present invention is limited, for example, powders, granules, troches, capsules, various types of health foods (including healthy foods), and the like. For example, an aqueous solution, a suspension, or the like. Nuclear savvy menopausal inhibitors can be used directly, and appropriate active ingredients (such as vitamins) can be used as needed. The nucleolipid in the climacteric inhibitor of the present invention The present climacteric inhibitor in the health food of the present invention may be appropriately selected as needed. The health food of the present invention is intended to inhibit the menopause of the present invention. The menopausal disorder inhibitor of the present invention is suitable for ingestion of, for example, 0.1 to 10 g per day, preferably in an amount of 0.2 to 5 g. In this case, the inhibitor of the disorder can be ingested one to three times a day, but the intake is appropriately increased or decreased depending on the symptoms of the menopausal disorder. It can be made into powders and nucleic acids. Nucleic acid (RNA) A large number of adenine and cytosine (C system is activated, there is no special gelatin, paste, healthy protein, protein as the amount of other white content or the content rate of the source In addition to the agent, it is also included, for example, equivalent: the age of the invention, the body weight, and (6) (6) 1309983. [Embodiment] The present invention will be described in more detail by the following examples. (1) Manufacture of the present invention The menopausal disorder inhibitor is manufactured by the following steps: 'The climacteric inhibitor of the present invention is made from the squid testis. i: The squid testis is taken before the squid testis to remove blood and water. After draining, add 300 ml. The water is ground and stirred to obtain a suspension. I i : The suspension is filtered by a powdering treatment to remove the solid matter such as the skin of the testis, and then spray-dried in a spray dryer to obtain a powdery substance.

Iii :洗淨及回收以乙醇洗淨上述之粉末狀物質，除去乙醇可溶解物及水份，減壓乾燥成粉末狀物，而得1 8 0 g之本更年期障礙抑制劑。如此所得之本更年期障礙抑制劑係含有核精蛋白爲主要成份之淡黃色粉末，其化學性質及物理性質係如下所述〇核酸含有率：25至50質量％蛋白質含有率：25至60質量％灰份含有率：5至15質量％寧海準反應（Ninhydrin reaction):陽性 -10- (7)1309983 (2 )本發明之更年期障礙抑制劑之評估手段爲客觀地評估更年期障礙之程度，使用更年期指數（ Kupperman index )。更年期指數係基於下述表1而計算。Iii: Washing and recovery The above-mentioned powdery substance was washed with ethanol to remove the ethanol soluble matter and water, and dried under reduced pressure to a powder to obtain 180 g of this menopausal inhibitor. The present menopausal disorder inhibitor thus obtained is a pale yellow powder containing nuclear protamine as a main component, and its chemical and physical properties are as follows: 〇 nucleic acid content: 25 to 50% by mass Protein content: 25 to 60% by mass Ash content: 5 to 15% by mass Ninhydrin reaction: positive-10-(7)1309983 (2) The evaluation method of the climacteric inhibitor of the present invention is to objectively evaluate the degree of menopausal disorder, using menopause Kupperman index. The menopause index is calculated based on Table 1 below.

-11 - (8) 1309983 表1:更年期指數之計算表症狀群症狀評估因素種類強度血管運動神經障礙般症狀臉發熱容易出汗腰或手腳冰冷感覺喘不過氣 3 · 2 · 1 · 0 4 知覺障礙般症狀手腳發麻手腳感覺遲鈍 3 · 2 · 1 · 0 2 失眠夜晚無法成眠即使夜晚能成眠，仍容易醒來 3 · 2 · 1 · 0 2 神經質容易興奮神經質 3 · 2 · 1 · 0 2 憂鬱爲小事煩惱容易憂鬱 3 · 2 · 1 · 0 1 暈眩頭暈或想吐 3 · 2 · 1 · 0 1 全身倦怠容易疲倦 3 · 2 · 1 · 0 1 關節痛·肌肉痛肩膀酸痛·腰痛· 手腳關節疼痛 3 · 2 · 1 · 0 1 頭痛頭痛 3 · 2 · 1 · 0 1 心悸亢進心臟動悸 3 · 2 · 1 · 0 1 犠行感感覺螞蟻爬行在皮膚上 3 · 2 · 1 · 0 1 -12- (9) 1309983 〈更年期指數之計算〉以下係說明更年期指數之計算方法。如表1所示之症候群之1 1種各症候，將症候（症狀）強度以0至3之數字表示。各數字之意味係如下所示。 3 :強 2 :中等程度 1 :弱〇 :無表1之症候群所屬之各症候係可再細分爲幾種症狀。以知覺障礙般症狀爲例，知覺障礙般症狀係分爲症狀「手腳發麻」與症狀「手腳感覺遲鈍」之2種。其次，關於各個症狀「手腳發麻」與症狀「手腳感覺遲鈍」，將症狀強度以0至3之數字表示。表1之症候群所屬之各症候之更年期指數係由下述之式（I )計算。式（I ):各種症狀強度之最高點X評估因素具體上，例如症狀「手腳發麻」之強度爲1，症狀「手腳感覺遲鈍」之強度爲0時，「知覺障礙般症狀」之更年期指數係1 (最高點）X2 (評估因素）=2。〈基於更年期指數（合計），判定更年期障礙的程度 > 表1所示之1 1種之各症候之更年期指數之合計〔更年期指數（合計）〕係成爲對更年期障礙之更年期指數。更年期障礙的程度係由更年期指數（合計），基於下述之基準而判定。 -13- (10) 1309983 3 5以上：重症 21至34 :中等症 1 6至2 0 :輕症〈更年期障礙治療效果之指標：停經指數之計算〉作爲更年期障礙治療效果之指標係使用停經指數。停經指數係由下述式（Π )而計算。式（Π ):治療後之更年期指數（合計）/治療前之更年期指數（合計）更年期障礙之治療效果係由停經指數，基於下述之基準而判定。 0.3以下：顯著〇 . 3至0.7 :有效 0.7以上：無效 (3 )本發明之更年期障礙抑制劑之評估結果 52歲至68歲之女性合計25人，攝取ig/日之本發明之更年期障礙抑制劑’於6 0天後，算出全體人員之更年期指數。結果如下述之表2至表4所示。 (11)1309983 眯 m-11 - (8) 1309983 Table 1: Calculation of Menopause Index Symptoms Symptoms Evaluation Factors Types Intensity Vasomotor Neurological Disorders Symptoms Facial fever Fever sweating or cold hands and feet Feeling breathless 3 · 2 · 1 · 0 4 Perception Obstacle-like symptoms, hands and feet, numb hands and feet, feeling sluggish 3 · 2 · 1 · 0 2 Insomnia can't sleep at night, even if you can sleep at night, it is easy to wake up 3 · 2 · 1 · 0 2 Neurotic is easy to excite neurotic 3 · 2 · 1 · 0 2 Melancholy troubles for small things, easy depression 3 · 2 · 1 · 0 1 dizziness, dizziness or vomiting 3 · 2 · 1 · 0 1 body burnout, easy fatigue 3 · 2 · 1 · 0 1 joint pain, muscle pain, shoulder pain, low back pain Hand and foot joint pain 3 · 2 · 1 · 0 1 Headache headache 3 · 2 · 1 · 0 1 palpitations into the heart 3 · 2 · 1 · 0 1 Sense of feeling ants crawling on the skin 3 · 2 · 1 · 0 1 -12- (9) 1309983 <Calculation of the Menopause Index> The following is a description of the calculation method for the menopause index. As for each of the symptoms of the syndrome shown in Table 1, the intensity of symptoms (symptoms) is represented by a number from 0 to 3. The meaning of each number is as follows. 3: Strong 2: Moderate 1: Weak 〇: None The symptoms of the syndromes in Table 1 can be subdivided into several symptoms. In the case of symptoms such as sensory disturbances, symptoms such as sensory disturbances are classified into two types: symptoms, numbness of the hands and feet, and symptoms of "slow hands and feet." Next, regarding the symptoms, "the numbness of the hands and feet" and the symptoms "the feelings of the hands and feet are slow", the symptom intensity is represented by a number from 0 to 3. The menopausal index of each symptom to which the syndrome of Table 1 belongs is calculated by the following formula (I). Formula (I): The highest point of each symptom intensity X evaluation factor Specifically, for example, the intensity of the symptoms "hands and feet numbness" is 1, the symptom "the feeling of hands and feet is slow" is 0, the menopausal index of "perceptual symptoms" Line 1 (highest point) X2 (evaluation factor) = 2. <Based on the menopause index (total), the degree of menopausal disorder is judged > The total of the menopausal index of each of the 11 types of symptoms shown in Table 1 (the menopause index (total)) is a menopausal index for menopausal disorders. The degree of menopausal disorder is determined by the menopause index (total) based on the following criteria. -13- (10) 1309983 3 5 or more: Severe 21 to 34: Moderate 1 6 to 20: Mildness: Index of treatment effect of menopausal disorder: calculation of menopausal index As an indicator of treatment effect of menopausal disorder, use of menopause index . The menstrual index is calculated by the following formula (Π). Formula (Π): Post-treatment menopausal index (total)/pre-treatment Menopause index (total) The therapeutic effect of menopausal disorder is determined by the menopause index based on the following criteria. 0.3 or less: significant 〇. 3 to 0.7: effective 0.7 or more: invalid (3) evaluation result of the climacteric disorder inhibitor of the present invention, a total of 25 women aged 52 to 68, ig/day of the invention inhibits menopause After 60 days, the agent's menopause index was calculated. The results are shown in Tables 2 to 4 below. (11)1309983 眯 m

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U Η 餾 55歲女性游〇〇 ——寸 —Ο (N Ο Ο 〇 ^― ·— fVj —— —*- ο ο m m ο ο ο ο 一一 - ΓΝί O CN CC Ο Ο 〇 Ο Ο 〇一 —CS 一——（ -Η — ο ο m m 一 — ο ο Ο 〇 87歲女性| 逛 Ο Ο Ο Ο 〇 Ο Ο 〇 ——04 〇一 fNJ ο ο ο ο ο ο ο —一 ο ο ο ο —— ^sD e Ο Ο Ο Ο 〇 Ο Ο 〇 *—1 >—1 (N O ο ο ο ο ο ο ο —— ο ο ο ο Ο 〇 id 55歲女性迤 ——Ο Ο <Ν —Ο (N ——fN —Ο (N ——— —一 ο ο Ο Ο ο ο ο ο Ο 〇 ο e <Ν Ο Ο 〇〇 ——(S (N (S 寸 (S o吋一—— —一 — ο ο ο ο 一— Ο 〇 (Ν (Ν 59歲女性班 Ο Ο Ο Ο Ο Ο Ο 〇 Ο Ο 〇 o o o ο ο ο ο ο ο ο ο ο ο ο ο ο 〇 C5 ο S ο ο ο ο ο Ο Ο 〇 (Ν (N 寸 ——<N -ο - ο ο (Ν (Ν —Η 一 ◦ ο Ο 〇二 58歲女性班 ο 一 ο ο 寸 0 — 01 Ο CM 呀 o o o ο ο ο ο ο ο ο —— ο ο —一 Ο 〇 (Ν S —< <Ν Ο fN ΟΟ —Ο (N Ο (N对 o o o ο ο ο 一一 CM (Ν (Ν <Ν ο ο ——' Ο 〇 55歲女性班 Ο Ο Ο Ο Ο Ο Ο 〇 Ο Ο 〇 o o o ίΝ (Ν CN ο ο —— —— ο ο ο ο Ο 〇对 S (Ν Ο Ο Ο 00 Ο Ο 〇 Ο Ο 〇 —(N 对 (Ν (Ν ο ο — —— ο ο 一一 Ο 〇卜 61歲女性班 Ο Ο Ο 一对 Ο Ο 〇 Ο Ο 〇 o o o Ο Ο Ο ο ο —一 ο ο Ο 〇 r- S ο ο ο —寸 Ο Ο 〇 Ο Ο 〇 o o o ο ο ο —— ΓΜ (Ν (Ν Γνΐ —— ο ο —— 二 59歲女性班 ο ο ο ο ο Ο Ο 〇 Ο Ο 〇 o o o ο ο ο ο ο —— —— ο ο ο ο Ο 〇 (Ν e ..ο ο 寸 Ο Ο 〇 Ο Ο 〇 o o o ο ο ο ο ο —— —— ο ο ο ο Ο 〇 oc 56歲女性班 ο ο ο ο ο Ο Ο 〇 Ο Ο 〇 o o o ο ο ο ο ο Ο Ο 一— ο ο ο ο Ο 〇 — —一〇〇呀 Ο Ο 〇 Ο Ο 〇 o o o "° Μ ο ο ο ο m m ο ο ο ο Ο 〇 00 驟 <1mtl P 體鹬 s ft： S IS ss 癒 3 S S 鹬崦链If壯磐娣鹽審K 簏 mu 鹬鞮s _ _壯 \fh K 騮峨娣 e n±^ rn m3 链 S 坩眾§5 堡®肚搭S K » | 魏® _麵壯 wmn i® ^ W- W » 七峨壯載姊)Κ m録 is _壯容易疲倦 :更年期指數賴按 S w1» a • ie mm ,咖蠢1 11W, :頭痛 :更年期指數心臟動悸更年期指數 ~Μ 键抝颦3S S踩 _肚 mn 更年期指數合計症候群血管運動神經障礙知覺障礙般病狀失眠神經質憂鬱頭暈全身倦怠關節痛· 肌肉痛頭痛心悸亢進蟻行感 -15- (12)1309983 58歲女性 >—1 — 〇〇 ^ Ο Ο 〇 ο ο ο —Ο (N ο ο ο ο ο ψ^, 一一 ο ο Ο 〇 Ο 〇 00 wm Ψ-^I psj >—1 ·—1 (Ν —Ο (N ο ο ο ο ο Ψ-^ τ-π (N CN ο ο Ο 〇 Ο 〇 ro 55歲女性麥 —Ο Ο 〇呀 —Ο (Ν —Ο (Ν O -- <N ο ο ο ο ο ο ο Ο 〇一― Ο 〇 Ο 〇一 Ο Ο Ο Ο 〇 —Ο (Ν Ο Ο Ο O — fN ο ο ο ο ο ο ο —'— r4 CM Ο 〇 Ο 〇卜 68歲女性鹚〇 — m Ο Ο Ο Ο — (Ν O r^t \D —-ο — ο ο m m m —— Ο 〇 —— Os S —〇 m — ^ CM Ο — (Ν 一（N寸 ο ο ο —— (Ν tN m m —'― —一 Ο 〇 «Ν m 64歲女性逛 fN (N — m 2 —— —(Ν寸 *— (N 寸 CN — CNJ ο ο 一 ” fN| CN ο ο CN (Ν Ο 〇 ON <N e m (N — m fN ^ — —(N tJ- m (Ν m ο ο (N CN (Ν (N ο ο <Ν (Ν Ο 〇 in m 57歲女性班 — O O O 寸 Ο Ο Ο Ο Ο Ο —Ο (N ο ο ο ο ο CM (N CM OJ ο ο Ο 〇 Ο 〇 o 一 o o o 寸 ο ο ο ο ο ο o o o ο ο ο ο ο tN (N CM (N ο ο Ο 〇 Ο 〇 00 52歲女性輕 Ο Ο (Ν Ο 00 (Ν —寸 ο ο ο o o o ο ο ο ο ο — CS CS ο ο Ο 〇 Ο 〇 Ο Ο ΓΝ| Ο 00 (Ν Ο呀 —Ο CNJ o o o ο ο ο ο ο H 一 <N rJ ο ο Ο 〇 Ο 〇 Γ- 53歲女性班 ο ο ο ο ο Ο Ο Ο Ο — (Ν O — <N ο ο ο ο ο o o —一 ο ο Ο 〇 Ο 〇 «〇 e ·— ζ^ι —0(Ν Ο CN廿〇 —< (Nj ο —— ο ο 一一 —— —:— 一— Ο 〇卜 53歲女性 ο ο ο ο ο Ο Ο Ο ο ο ο o o o ο ο ο ο ο o o r4 〇J ο ο Ο 〇 Ο 〇 CN 症 ο ο ο ο ο ο ο ο ο ο ο o o o ο ο ο ο ο o o (Ν (N ο ο Ο 〇 Ο 〇 o 56歲女性 ο ο ο ο ο ο ο ο ——(Ν o o o ο ο ο ο ο T—— (Ν (N ο ο Ο 〇 Ο 〇 •/"l g ο ο ο ο ο ο ο ο ——(Ν o o o ο ο ο ο ο w — CM fN 一一 Ο 〇 Ο 〇更年期指數合計 6 騷 Μ * 餾鏟 !t S US SS « B阼豳踩鎞崦锊胩磐妫B馨W 葚 mmm 鹬飽s S S UU VLU wj ΠΤ1 up 圜掷 s OH S *ga> 撼s w 線 w | 截_(餘峨鍵肚 ίφ ft 1»< 麵1 藏 i® g 條_ 05 七嘛壯翁娣w +]錄 i班 is s w 容易疲倦更年期指數艇谈 ε ΙΕ^ ΠΕΕ s i!f ,um «s i扮 m 1¾ 頭痛 1 更年期指數 1 心臟動悸更年期指數 Ή 键相 S錄 |35 mu 症候群血管運動神經障礙知覺障礙般病狀失眠神經質i m Μ 頭暈：全身倦怠關節痛· 肌肉痛頭痛心悸亢進犠行感帐担U Η 55 55 55 55 55 55 55 55 55 寸寸寸寸寸寸寸寸寸寸 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN O O O CN O CN —CS 一——(-Η—— ο ο mm 一— ο ο Ο 〇 87-year-old woman | Ο Ο Ο Ο 〇Ο Ο 〇 04 04 f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f ——^sD e Ο Ο Ο Ο 〇Ο Ο 〇*—1 >—1 (NO ο ο ο ο ο ο ο —— Ο (N ——fN —Ο (N ——— — ο ο Ο Ο ο ο ο ο Ο 〇ο e <Ν Ο Ο 〇〇——(S (N (S inch (S o吋一——一 5 5 Ν Ν Ν 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ο ο ο Ο Ο 〇 (Ν (N inch - <N - ο - ο ο (Ν (Ν Η Η ◦ ο 〇 58 58 58 58 58 58 58 58 58 58 寸寸 — — — — — — — — — — — — — ο ο ο ο ο ο —— ο ο — 一 Ο Ν (Ν S —<<Ν Ο fN ΟΟ —Ο (N Ο (N vs ooo ο ο ο 一一CM (Ν Ν Ν Ν 〇 —— ' 〇〇〇〇〇〇〇〇〇 oo oo oo Ο 〇Ο Ο ooooo Ν Ν CN ο ο —— —— ο ο ο ο Ο 〇 S S Ν 00 00 00 00 00 00 00 ( ( ( ( ( ( ( ( ( ( 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 61 Ο - oo Ο oo oo oo oo oo oo oo oo oo oo - - oo oo oo oo - - - 一 - - - - - - - - - - - - oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo Γ ΐ —— 二 —— 二二 oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν 56 Ο 〇ooo ο ο ο ο ο 56 56 56 56 56 56 56 56 56 56 56 56 56 56 56 56 oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo 〇〇〇 oo oo oo oo Ο 〇 oo ooo "° Μ ο ο ο ο ο ο ο ο ο ο 1 1 1 1 S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S Strong salt K 簏mu 鹬鞮s _ _ 壮 \fh K 骝峨娣en±^ rn m3 chain S 坩 § 5 堡肚肚 SK » | Wei _ _ face strong wmn i® ^ W- W » Seven strong姊)Κ m recorded is _ Zhuang easy to get tired: menopause index depends on S w1» a • ie mm, coffee stupid 1 11W, : headache: menopause index heart beat menopause index ~ Μ key 拗颦 3S S step _ belly mn menopause index Total Symptoms Vascular motor neurological disorders Perceptual disorders Symptoms Insomnia Neurological depression Dizziness Systemic burnout Joint pain • Muscle pain Headache 悸亢行 Sense -15- (12) 1309983 58-year-old female> _1 — 〇〇^ Ο Ο 〇ο ο ο —Ο (N ο ο ο ο ο ψ^, 一一ο ο Ο 〇Ο 〇00 wm Ψ-^I psj >—1 ·—1 (Ν Ο (N ο ο ο ο ο Ψ-^ Τ-π (N CN ο ο Ο 〇Ο 〇ro 55-year-old female wheat - Ο 〇〇 Ο Ο Ν Ν -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 68 Ο Ο Ο 〇〇 Ο Ο Ν — — — — — — — — 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 68 ^t \ D —- ο — ο ο mmm —— Ο 〇 — Os S — 〇m — ^ CM Ο — (Ν一(N inch ο ο ο —— (Ν tN mm — '― —一Ο 〇«Ν m 64 Year-old female strolling fN (N - m 2 - (Ν inch * - (N inch CN - CNJ ο ο 一" fN| CN ο ο CN (Ν Ο 〇 ON <N em (N — m fN ^ — — (N tJ- m (Ν ο ο ο N N N 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 57 CM (N CM OJ ο ο Ο 〇Ο 〇o a ooo inch ο ο ο ο ο ο o oo oo oo N 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 52 (Ν 寸 ο ο ο CS CS CS CS CS CS CS CS CS CS CS 00 00 00 00 00 00 J J J J J J J J J J J J J J J J J J J J J J J J J J J J 一一一一一一一一一一一一一一一一一一一一一一一一一一一一〇Ο 〇Γ - 53-year-old female class ο ο ο ο ο Ο Ο Ο Ο — (Ν O — <N ο ο ο ο ο oo — ο ο Ο 〇Ο 〇«〇e · — ζ^ι —0 (Ν Ο CN廿〇—< (Nj ο —— ο ο 一一——————一— Ο 〇 53 53-year-old woman ο Ο Ο ο ο ο oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo N ο ο Ο 〇Ο 〇o 56-year-old female ο ο ο ο ο ο ο ο —— (Ν ooo ο ο ο ο ο T—— (Ν (N ο ο Ο 〇Ο 〇•/" lg ο ο ο ο ο ο ο ο ——(Ν ooo ο ο ο ο ο w — CM fN 一〇Ο 〇〇 menopause index total 6 Μ Μ * Distillation shovel! t S US SS « B阼豳阼豳B馨W 葚mmm ss S UU VLU wj ΠΤ1 up 圜 s s OH S *ga> 撼sw line w | _ _ _ 峨峨 ί ί ft 1»< face 1 hidden i® g _ 05 VII壮娣娣 w +] recorded i class is sw easy to get tired menopause index boat talk ε ΙΕ ^ ΠΕΕ si!f, um «si play m 13⁄4 headache 1 menopause index 1 heart beat menopause index Ή key phase S record | 35 mu syndrome Vascular motor disorder, sensory disorder, pathological insomnia, neurotic im Μ dizziness: generalized burnout, joint pain, muscle pain, headache, heart palpitations, sensation

N m. 展藻艇N m. Algae

Ws 鹬 16 (13)1309983 Μ 担 life 蘅 ΜWs 鹬 16 (13)1309983 Μ life life 蘅 Μ

S 蘧S 蘧

S 壯合計〇s 〇〇〇 CC 00 卜寸 (N 卜〇\ ΓΜ <N 'sO m \〇 r*-i «Ti ΓΟ 卜 (N On 卜一〇〇 rs 〇\ m »/Ί Γ〇 <N oc σν 00 二 — yn •n (N •/Ί (N oc 00 〇〇 00 〇〇 — — cn 56歲女性鹚〇〇〇 ” 对 —Ο (N Ο Ο 〇 o o o (了) ο ο —— — o o ο ο Ο 〇 σν S ο ο (N rn ^ —CN节 Ο — (N —r-j m ο ο 04 CN —— o o — Ο 〇 m 60歲女性班 Ο Ο Ο Ο 〇 Ο — (N Ο Ο 〇 o o o ο ο ο ο ο o o <N (N o o ο ο Ο 〇 rj- U Ο Ο Ο Ο 〇 O CN对 Ο Ο 〇 o o o ο ο ο ο ο o o ro m o o ο ο Ο 〇卜 55歲女性班 —Ο Ο 〇对 Ο Ο 〇 ——(Ν o o o ο-- ο ο o o —— o o ο ο Ο 〇 00 fc fS (Ν Ο Ο 00 Ο Ο 〇 <Ν ίΝ 对 o o o ο-- ο ο —一 CN ΟΊ 一— ο ο Ο 〇卜 60歲女性鹚 —<Ν Ο Ο 00 Ο Ο 〇 —ίΝ Tf· 〇 eN廿 ο ο ο ο ο o o CN <N —— ο ο Ο 〇 fc • ΓΝ Ο Ο 00 Ο Ο 〇 (N (N (N O fN (N ο ο ο ο ο o o (N ΓΜ — ο ο Ο 〇 σ\ 54歲女性班 —(Ν Ο <Ν 00 Ο Ο 〇 O — CM O — iN ο ο ο ο ο 一— —— —— ο ο Ο 〇 •ο S —(Ν Ο (Ν 00 Ο Ο 〇 ——fN O — <N ο ο ο ο ο (N CM m r^i o o ο ο Ο 〇卜 54歲女性逛 Ο Ο — Ο 对 Ο Ο 〇 O 一 CN o o 〇 ο ο ο ο ο (N (N m m o o ο ο Ο 〇二 fc 一〇 — 〇 Tj* —Ο (N O — (N —Ο <N ——— —一 <N fN fN (N o o ο ο Ο 〇 Ό 54歲女性班 Ο Ο Ο Ο Ο Ο Ο 〇 o o o o o o ο ο ο ο ο o o ΓΜ CM o o ο ο Ο 〇 (Ν Ο Ο Ο Ο Ο Ο Ο 〇 o o o o o o ο ο ο ◦ ο ◦ o m m o o ο ο Ο 〇更年期指數合計 3 種類 * 您 S fc g 嫉 2S ft 3 Hf- S 餾_锊}^肚磐娣g韹w is mmm 鎞蹈踩 S _进 Hr Hf> )&( 长 a n® 娣 e OH盛 ί^ττ1 il>7 链黑録銮jg壯擦E W 容易興奮神經質更年期指數輩 S 鹧®™ 條_ s 脈拗蚁 +ia 1n? s m[ im/ 容易疲倦更年期指數 s eS m m 鹽s «ss 幽肚 is κ 頭痛更年期指數心臟動悸更年期指數 -Η 樓坩 It 聲S 邂® SS nm 症候群血管運動神經障礙知覺障礙般病狀失眠神經質憂鬱頭暈全身倦怠關節痛· 肌肉痛頭痛心悸亢進蟻行感 -17- (14) 1309983 (4 )檢討本發明之更年期障礙抑制劑之評估結果由表4之更年期指數之合計欄之數値，計算對應全體女丨生2 5人之停經指數。結果係如下所示。停經指數：23 7/3 6 1与0 · 6 6 (有效）亦即，因爲停經指數爲0 · 6 6，係於0.3至0.7之範圍內 ’所以判定由本發明之更年期障礙抑制劑係有效地治療更年期障礙。S 壮〇〇〇〇〇 CC 00 卜 inch (N 〇〇 \ ΓΜ <N 'sO m \〇r*-i «Ti ΓΟ 卜 (N On 卜一〇〇rs 〇\ m »/Ί Γ〇 <N oc σν 00 II - yn •n (N •/Ί (N oc 00 〇〇00 〇〇 – cn 56-year-old female 鹚〇〇〇) Ο Ο (N Ο Ο 〇ooo ( ) ο ο —— oo ο ο Ο 〇σν S ο ο (N rn ^ —CN 节Ο — (N —rj m ο ο 04 CN —— oo — Ο 〇m 60-year-old female class Ο Ο Ο 〇Ο — (N Ο Ο ooooo ο ο ο ο ο oo oo j CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN oo oo oo CN CN CN 55 oo 55 55 55 55 55 55 55 55 55 55 55班班〇〇〇〇〇〇 Ν Ν Ν Ν 〇 Ν Ν f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f 00 o f f f f f o o o f f f f o o o f f f f o o o —一CN ΟΊ一— ο ο Ο 〇 60 60 year old female 鹚—& Ν Ν Ο 00 00 Ο Ο 〇 — Ν Ν Tf· 〇eN廿ο ο ο ο ο oo oo CN <N —— ο ο Ο 〇fc • ΓΝ Ο 00 00 Ο Ο 〇 (N (N (N (NO fN (N ο ο ο ο ο oo (N ΓΜ — ο ο Ο 〇σ\ 54-year-old female class - (Ν Ο <Ν 00 Ο Ο 〇O — CM O — iN ο ο ο ο ο —— —— — ο ο 〇 ο•ο S —(Ν Ο (Ν 00 Ο Ο 〇 - fN O — <N ο ο ο ο ο (N CM mr^ioo ο ο Ο 〇 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 54 Ο Ο 〇O a CN oo 〇ο ο ο ο ο (N (N mmoo ο ο Ο f f f f 〇〇 j j j j j NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO NO f oo 〇Ό 〇Ό 〇Ό oo 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό oo 〇Ό 〇Ό 〇Ό 〇Ό 〇Ό oo CM CM CM CM CM oo CM CM CM CM CM CM CM CM CM CM oo CM oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo ο ◦ ο ◦ ommoo ο ο Ο 〇 Menopause Index Total 3 Categories* You S fc g 嫉2S ft 3 Hf- S Distillation _锊}^ Intestines g韹w is mmm Stepping on S _ into Hr Hf>)&; (长an® 娣e OH Shengί^ττ1 il>7 chain black record 銮jg strong rub EW easy to excite neurotic menopause index generation S 鹧®TM strip _ s pulse ant +ia 1n? sm[ im/ easy to fatigue menopause Index s eS mm s «ss 肚 is is κ headache menopausal index heart dysfunction menopausal index - 坩坩 It sound S 邂 ® SS nm syndrome vasomotor neurological disorder sensory disorder insomnia neurotic depression dizziness body burnout joint pain · muscle pain headache heart sputum ants Sense -17- (14) 1309983 (4) Review of the evaluation results of the menopausal inhibitors of the present invention From the total number of the menopausal indices in Table 4, calculate the menstruation index corresponding to 25 female students. The results are as follows. Menopause index: 23 7/3 6 1 and 0 · 6 6 (effective), that is, because the menstrual index is 0 · 6 6 within the range of 0.3 to 0.7, so it is determined that the menopausal inhibitor of the present invention is effective Treat menopausal disorders.

另外，關於症候群所屬之各症候，由上述式（Π )所計算之指數係如下所示。此等指數係成爲對各種症候之治療效果之判斷基準。In addition, regarding each symptom to which the syndrome belongs, the index calculated by the above formula (Π) is as follows. These indices are the basis for judging the effects of various symptoms.

血管運動神經障礙：86/128与0.67 知覺障礙般症狀：18/36 = 0.50 失眠：3 0/48 与 0.63 神經質：3 0 / 3 8与0.7 9 憂鬱：9/15 = 0.6 頭暈：2/6与0.33 全身倦怠：16/25与0.64 關節痛、肌肉痛：3 6/4 8 = 0.75 頭痛：5”0=〇.50 心悸亢進：3/84 0.38 蟻行感（formication) : 1/3与〇·33 對於各種症候之治療效果雖不均勻’但本發明之更年期障礙抑制劑係有效地抑制大範圍的症候。 -18-Angiopathy: 86/128 vs. 0.67 Perceptual symptoms: 18/36 = 0.50 Insomnia: 3 0/48 and 0.63 Neuroticism: 3 0 / 3 8 and 0.7 9 Melancholy: 9/15 = 0.6 Dizziness: 2/6 With 0.33 systemic burnout: 16/25 and 0.64 joint pain, muscle pain: 3 6/4 8 = 0.75 headache: 5"0 = 〇.50 palpitations: 3/84 0.38 ant sense (formation): 1/3 with 〇·33 Although the therapeutic effects on various symptoms are not uniform, the cerebral dysfunction inhibitor of the present invention effectively suppresses a wide range of symptoms.

Claims

1309983 (1) 曰Fixed ιΗΙpage

Patent Application No. 93 1 34486 Patent Application Revision of Chinese Patent Application Revision of the Republic of China on October 27, 1997 1. A climacteric disorder inhibitor characterized by containing a nucleic acid containing content of 25 to 50% by mass and protein 25 ~60% by mass of the ratio of nuclear protamine. 2. For example, the climacteric inhibitor of the climacteric term of claim 1, wherein the nuclear protamine is obtained from the nuclear testis of the fish. 3. For the treatment of climacteric barriers in the second paragraph of the patent application, the fish is salmon, trout, squid or squid. 4. A health food characterized by containing an effective amount of a menopausal disorder inhibitor as claimed in claim 1