KR20040019513A - Health assistant functional foodstuffs containing phytoestrogens derived from pomegranate and preparing methods thereof - Google Patents
Health assistant functional foodstuffs containing phytoestrogens derived from pomegranate and preparing methods thereof Download PDFInfo
- Publication number
- KR20040019513A KR20040019513A KR1020020051077A KR20020051077A KR20040019513A KR 20040019513 A KR20040019513 A KR 20040019513A KR 1020020051077 A KR1020020051077 A KR 1020020051077A KR 20020051077 A KR20020051077 A KR 20020051077A KR 20040019513 A KR20040019513 A KR 20040019513A
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- KR
- South Korea
- Prior art keywords
- weight
- dietary supplement
- pomegranate
- menopausal
- estrogen
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L33/17—Amino acids, peptides or proteins
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
- A23L33/25—Synthetic polymers, e.g. vinylic or acrylic polymers
- A23L33/26—Polyol polyesters, e.g. sucrose polyesters; Synthetic sugar polymers, e.g. polydextrose
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
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- A23V2250/00—Food ingredients
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- A23V2250/21172—Soy Isoflavones, daidzein, genistein
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Abstract
Description
본 발명은 석류 유래의 피토에스트로겐을 함유하는 기능성 건강보조식품 및 그 제조방법에 관한 것이며, 더욱 상세하게는, 다량의 피토에스트로겐을 함유하는 석류 추출물을 포함하는 기능성 건강보조식품 및 그 제조방법에 관한 것이다.The present invention relates to a functional dietary supplement containing phytoestrogens derived from pomegranate and a method for producing the same, and more particularly, to a functional dietary supplement comprising a pomegranate extract containing a large amount of phytoestrogens and a method for producing the same. will be.
일반적으로 내분비계는 생체의 항상성 유지, 생식, 발생, 행동 등에 관여하는 각종 호르몬을 생산·분비하는 기관계로서 선(腺), 호르몬, 표적세포(target cell)로 구성되며, 여기서 생산되는 호르몬은 혈액을 통해 체내를 순환하며 표적이 되는 각 세포 및 조직에 정보 및 명령을 전달하여 성장 및 발육, 암수분화 등에 관여한다.In general, the endocrine system is an organ system that produces and secretes various hormones involved in maintaining homeostasis, reproduction, development, and behavior of a living body, and is composed of gland, hormones, and target cells. Through the body circulates through the information and commands to each target cell and tissue involved in growth and development, cancer and differentiation.
이러한 내분비계 호르몬의 하나인 에스트로겐(estrogen)은 체내에서 콜레스테롤로부터 합성되며, 분비원(分泌源)은 주로 난소의 난포(卵胞) 및 황체(黃體)이고 임신시의 태아 태반계, 부신(副腎)·정소(精巢) 등에서도 분비된다. 난소에서의 에스트로겐 분비는 뇌하수체전엽(腦下垂體前葉)에서 분비되는 성선자극(性腺刺戟)호르몬 (gonadotropin)이 생식기관에 신호를 전달하면 월경주기를 조절하고 임신을 가능케 하는 호르몬인 난포자극호르몬(follicle stimulating hormone;FSH)과 황체형성호르몬 (Lutenizing hormone;LH)이 분비되고, 이는 다시 난소에 작용하여 에스트로겐 (estrogen)과 프로게스테론(progesterone)을 분비하게 한다. 에스트로겐은 월경주기 전반부에 자궁내막을 자극해 수정란이 착상할 수 있도록 자궁내막이 두꺼워지도록 하고 혈액공급량을 증가시키며, 후반부에는 프로게스테론이 분비되어 자궁내막이 착상을 이루는데 보다 좋은 상태가 되도록 한다. 즉, 에스트로겐은 자궁내막의 증식, 자궁근의 발육, 제2차 성징(性徵)의 발현, 월경주기 성립의 매개, 임신시의 모체변화 야기, 유선관(乳腺管)의 증식분비 촉진 등에 관여하는 대표적인 여성호르몬이나, 신체의 다른 여러 부위에도 광범위한 영향을 미친다.Estrogen, one of these endocrine hormones, is synthesized from cholesterol in the body. The secretory sources are mainly follicles and corpus luteum of the ovary, and fetal placenta, adrenal gland during pregnancy. It is also secreted from the testis. Estrogen secretion in the ovary is when the gonadotropin secreted from the anterior pituitary gland transmits a signal to the reproductive organs, which regulates the menstrual cycle and enables pregnancy. Follicle stimulating hormone (FSH) and luteenizing hormone (LH) are secreted, which in turn act on the ovary, releasing estrogen and progesterone. Estrogen stimulates the endometrium in the first half of the menstrual cycle to thicken the endometrium and increase blood supply so that the fertilized egg can be implanted, and progesterone is secreted in the second half to make the endometrium better. In other words, estrogen is involved in the growth of the endometrium, the development of the uterine muscle, the development of secondary sexual characteristics, the mediation of the menstrual cycle, the maternal change during pregnancy, and the promotion of the proliferation of the mammary gland. Representative female hormones, or other parts of the body have a wide range of effects.
상기한 에스트로겐은 에스트라디올(estradiol), 에스트론(estrone), 에스트리올(estriol) 등을 총칭하며, 이 중에서 에스트라디올이 가장 강력한 것으로 알려져 있다. 에스트로겐은 수용체를 매개로 하여 기능을 하며 주로 간장에서 대사(代謝)를 받아, 포합성(抱合性) 에스트로겐이 되어 소변으로 배설된다.The estrogens are estradiol, estrone, estriol and the like generically, among which estradiol is known to be the strongest. Estrogens function through receptors and are primarily metabolized in the liver and are excreted in the urine as synthetic estrogens.
폐경 전의 여성에 있어 난소는 에스트로겐의 주요 공급원이다. 주요 분비 생성물은 난포막 세포에 의해 공급되는 안드로겐 전구체로부터 과립막 세포에 의해 합성되는 에스트라디올이다. 분비된 에스트라디올은 에스트론으로 가역적으로 산화되고 에스트로겐은 에스트리올로 전환될 수 있다. 17-히드록시스테로이드 탈수소화효소에 의해 촉매화되는 간에서 에스트론과 에스트라디올 사이의 상호전환이 주로 일어난다. 남성 및 폐경 후 여성에 있어서 에스트로겐의 주요 공급원은 지방조직이다. 이러한 조직에서 에스트론은 부신피질에 의해 분비되는 데하이드로에피안드로스테론으로부터 합성되며, 따라서 지방 조직에 의한 에스트로겐의 분비는 안드로겐 전구체를 이용함으로써 부분적으로 조절될 수 있는 것으로 알려져 있다(Mendelson, C.R. 및 Simpson, E.R., 52:169-176, (1987)).In premenopausal women, the ovary is a major source of estrogen. The main secretion product is estradiol, synthesized by granulosa cells from the androgen precursor supplied by the follicular membrane cells. Secreted estradiol can be reversibly oxidized to estrone and estrogen can be converted to estriol. Interconversion between estrone and estradiol occurs mainly in the liver catalyzed by 17-hydroxysteroid dehydrogenase. In men and postmenopausal women, the main source of estrogen is adipose tissue. In these tissues, estrone is synthesized from dehydroepiandrosterone secreted by the adrenal cortex, so it is known that the secretion of estrogen by adipose tissue can be partially regulated by using androgen precursors (Mendelson, CR and Simpson, ER, 52: 169-176, (1987)).
폐경전의 여성에 있어서, 난소에 의해 생성되는 17β-에스트라디올은 주요 순환성 에스트로겐이다. 혈청 에스트라디올의 농도는 사춘기 소녀에서는 낮고, 초경인 소녀에게서는 높게 나타난다. 여성에 있어서 에스트라디올의 농도는 난포기의 약 100pg/㎖(367pmol/ℓ)로부터 배란기의 약 600 pg/㎖(2200pmol/ℓ)까지이다. 임신 기간 동안에는 거의 20,000pg/㎖(70,000pmol/ℓ)까지 상승하게 된다. 폐경기 후, 혈청 에스트라디올의 농도는 비슷한 나이의 남성에서 나타나는 농도(5~20pg/㎖)와 비슷한 수준으로 떨어지는 것으로 보고되어 있다(Yen, S.S.C. 및 Jaffe,R.B., 3rd ed. Philadelphia: W.B. Saunders, (1991)).In premenopausal women, 17β-estradiol produced by the ovary is the major circulating estrogen. Serum estradiol levels are low in puberty girls and high in tungsten girls. In women, the concentration of estradiol ranges from about 100 pg / ml (367 pmol / l) of the follicular phase to about 600 pg / ml (2200 pmol / l) of the ovulatory phase. During gestation, it will rise to nearly 20,000 pg / ml (70,000 pmol / l). After menopause, serum estradiol concentrations have been reported to drop to levels comparable to those seen in men of comparable age (5-20 pg / ml) (Yen, SSC and Jaffe, RB, 3rd ed. Philadelphia: WB Saunders, ( 1991).
여성이 폐경기에 접어들면, 난소가 노화됨에 따라 하수체성 고나도트로핀 (gonadotropin)(여포-자극 호르몬(FSH) 및 황체형성 호르몬(LH))에 대한 반응이 감소하고, 이로 인해 초기 난포기가 더욱 단축되어 월경 주기가 더욱 단축되며, 배란기가 더욱 단축되고, 프로게스테론 생성이 감소되며, 사이클이 더욱 불규칙하게 된다. 결국, 여포가 반응하지 못하게 되어 에스트로겐을 생성하지 못하게 된다. 에스트로겐의 분비 감소는 여성의 비뇨생식계통 뿐만 아니라 신체전반에 걸쳐 큰 영향을 미치게 되며, 배란이 중단되어 월경이 사라지는 것을 폐경이라 하고, 폐경 또는 그 이전에 호르몬의 감소로 인한 폐경기 증상이 나타나게 된다.As a woman enters menopause, as the ovary ages, the response to pituitary gonadotropin (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) decreases, resulting in early follicular Further shortening results in shorter menstrual cycles, shorter ovulation phases, reduced progesterone production, and more irregular cycles. Eventually, the follicles will not react and will not produce estrogens. Reduced secretion of estrogen has a great effect not only on the genitourinary system, but also throughout the body. Menopause is stopped when ovulation is stopped, and menopausal symptoms due to hormone reduction before or after menopause appear.
또한, 40세 이전에 발생하는 미숙 폐경은 원인 미확인의 난소 부전으로 통칭되며, 이는 다량의 장기간에 걸친 흡연이나, 고해발 고도에서의 거주, 영양 불량 등과 관련이 있는 것으로 믿어지고 있다, 한편, 인위적 폐경은 난소적출술, 화학요법, 골반에 대한 방사선 조사, 또는 난소에 대한 혈액 공급을 저하시키는 임의의 과정으로부터 초래될 수 있다.In addition, immature menopause occurring before the age of 40 is commonly referred to as unidentified ovarian failure, which is believed to be associated with a large amount of long-term smoking, high altitude residence, and malnutrition. Menopause can result from ovarian extraction, chemotherapy, radiation to the pelvis, or any process that lowers the blood supply to the ovaries.
폐경기 이후 여성에서는 에스트로겐의 급속한 감소로 인하여, 심리학적 및 감성적 징후, 예컨대 피로, 흥분, 불면, 집중력 저하, 우울증, 기억 상실, 두통, 근심 및 신경과민이나 소심증 등이 발생할 우려가 현저히 높아지게 되며, 재발성 안면 홍조에 의한 수면 방해에 따른 피로와 흥분, 간헐성 현기증, 감각이상, 심계항진 및 빈맥, 메스꺼움, 변비, 설사, 관절통, 근육통, 수족 냉증 및 체중 증가 현상의 발생 우려 또한 현저히 높아지게 된다. 또한, 골다공증이 쉽게 유발될 뿐 아니라, 심장병, 고혈압, 뇌졸중 등의 심혈관계 질환으로 인한 사망률도 증가한다(Kalin MF & Zumoff B. Steroids 55:330-352, 1990). 또한, 피부 및 비뇨생식계통의 변화를 초래하며, 자가면역성 질환, 백내장 및 대장암 등의 발병 가능성이 높아지게 된다.In postmenopausal women, the rapid decrease in estrogens significantly increases the risk of developing psychological and emotional signs such as fatigue, excitement, insomnia, poor concentration, depression, memory loss, headache, anxiety, and nervousness or timidity, and recurrence. Fatigue and excitement due to sleep disturbance, intermittent dizziness, paresthesia, palpitations and tachycardia, nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and legs, and weight gain are also significantly increased. In addition, osteoporosis is not only easily induced, but also mortality due to cardiovascular diseases such as heart disease, high blood pressure and stroke is increased (Kalin MF & Zumoff B. Steroids 55: 330-352, 1990). In addition, it causes changes in the skin and urogenital system and increases the likelihood of developing autoimmune diseases, cataracts and colorectal cancer.
여성이 폐경기에 접어들어 에스트로겐이 현저히 감소하게 되면, 예컨대, 질 점막 및 외음부 피부는 더욱 얇아지고, 통상의 박테리아 군상이 변하고, 소음순, 클리토리스, 자궁 및 난소의 크기가 감소하는 등 저부 생식관내에 현저한 변화를 초래하게 된다. 따라서, 질 점막의 염증(위축성 질염), 빈뇨 및 급뇨, 질 건조증 및 성교불쾌증을 유발시킬 수 있다. 또한, 골반 근육의 색조 소실, 실금증, 방광염및 질염으로 발전되는 경향이 나타난다.Significant decreases in estrogen as women enter menopause, such as thinning of the vaginal mucosa and vulva skin, changing normal bacterial colonies, and decreasing the size of labia minora, clitoris, uterus and ovaries It causes a change. Thus, inflammation of the vaginal mucosa (atrophic vaginitis), frequent urination and urgency, vaginal dryness and sexual dysphoria can be caused. In addition, there is a tendency to develop hue loss of the pelvic muscles, incontinence, cystitis and vaginitis.
안면홍조 및 발한은 폐경기 여성 중 약 75% 정도가 경험하게 되는 것으로 알려져 있다. 홍조 현상은 통상적으로 폐경 중 또는 폐경 후에 발생하며, 에스트로겐 결핍과 직접 관련되어 있다. 그 대부분은 1년 이상 안면 홍조가 지속되며, 25 내지 50%는 5년 이상 안면 홍조가 지속된다. 안면홍조는 안면과 목, 가슴 상부에 집중되는 갑작스러운 열감으로 시작되며 피부가 적색으로 변하고, 이러한 열감은 30초 내지 5분간 지속되며, 흔히 다량의 발한을 수반하고, 때로는 심계 항진도 수반되며, 통상적으로는 발한과 오한이 수반된다(Casper, RF, Yen, SSC. Neuroendocrinology of menopausal flushes: An hypothesis of flushmechanism. Clin Endocrinol 1985; 22:293).Hot flashes and sweating are known to occur in about 75% of postmenopausal women. Flushing typically occurs during or after menopause and is directly related to estrogen deficiency. Most of them persist for more than 1 year and 25 to 50% of them last more than 5 years. Hot flashes begin with a sudden hot flash that concentrates on the face, neck, and upper chest, the skin turns red, and this hot flash lasts 30 seconds to 5 minutes, often involves a lot of sweating, sometimes accompanied by palpitations, Usually accompanied by sweating and chills (Casper, RF, Yen, SSC. Neuroendocrinology of menopausal flushes: An hypothesis of flushmechanism. Clin Endocrinol 1985; 22: 293).
이러한 안면홍조 현상은 매일 1, 2회 정도, 또는 많을 경우에는 주야로 시간당 1회 정도의 범위일 수 있으며, 통상적으로는 하루에 수 차례씩 일어난다. 안면홍조 현상은 수면 각성을 일으켜서 수면을 방해하며, 수많은 여성들이 다량의 발한을 경험하게 되므로 사회 생활에 있어 상당히 당혹스러운 문제를 초래할 수 있다. 안면홍조 현상은 에스트로겐 금단에 의해 시상하부의 열 조절 기능장애에 기인하는 것으로 믿어지고 있다. 안면홍조 현상이 황체화 호르몬의 펄스와 동시에 발생하는 점으로부터 온도 변화가 매개되는 것으로 보고되어 있다(Casper, RF, Yen, SSC, Wilkes, MM. Menopausal flushes: ANeuroendocrine link with pulsatile luteinizing hormone secretion. Science 1979; 205:823 및 Tataryn, IV. Meldrum,DR, Lu, KH, et al. LH, FSH and skin temperature during the menopausalhot flash. J Clin Endocrinol Metab 1979;49:152). 안면홍조 현상의 개시 메카니즘은 내인성 오피오이드 펩타이드 금단 현상으로서, 에스트로겐은 중추 오피오이드 펩타이드 활성을 증가시키는 한편, 폐경은 내인성 중추 오피오이드 활성의 감소 또는 상실과 관련되어 있는 것으로 밝혀져 있다(Reid, RL, Quigley, ME, Yen, SS. The disappearance of opiodidergic regulation of gonadotropin secretionin postmenopausal women. J Clin Endocrinol Metab 1983; 57:1107).Such hot flashes may range from once or twice daily, or in many cases once daily during the day, usually several times a day. Hot flashes can cause sleep arousal and disturb sleep, and many women experience a lot of sweating, which can lead to quite embarrassing problems in social life. Hot flashes are believed to be due to dysfunction of the hypothalamus due to estrogen withdrawal. Temperature changes are reported to be mediated by the occurrence of hot flashes at the same time as the pulse of luteinizing hormone (Casper, RF, Yen, SSC, Wilkes, MM. Menopausal flushes: ANeuroendocrine link with pulsatile luteinizing hormone secretion.Science 1979 205: 823 and Tataryn, IV.Meldrum, DR, Lu, KH, et al. LH, FSH and skin temperature during the menopausalhot flash.J Clin Endocrinol Metab 1979; 49: 152). The initiation mechanism of hot flashes is endogenous opioid peptide withdrawal, with estrogens being found to increase central opioid peptide activity, while menopause is associated with a decrease or loss of endogenous central opioid activity (Reid, RL, Quigley, ME). , Yen, SS.The disappearance of opiodidergic regulation of gonadotropin secretionin postmenopausal women.J Clin Endocrinol Metab 1983; 57: 1107).
현재, 상기한 안면홍조 현상을 방지하거나 치료하는 데 있어서 가장 효과적인 공지된 방법은 에스트로겐을 투여하여 결핍된 에스트로겐을 보충해 주는 것으로 알려져 있다.Currently, the most effective known methods for preventing or treating the hot flashes are known to supplement estrogens by administering estrogens.
또한, 폐경기의 여성에서 발생 빈도가 높은 심장혈관의 아테롬성 동맥경화증 (atherosclerosis)에 대한 감수성은 혈중의 에스트로겐 농도를 높이는 것에 의해 효과적으로 저감시킬 수가 있는 것으로 보고되어 있다(Stout D.W., 1982). 한편, 아테롬성 동맥경화증을 갖고 있는 토끼에 대한 실험 결과, 에스트로겐은 혈액중의 지질 함량을 낮추고 항아테롬성(antiatherosclerotic) 효과를 나타내는 것으로 확인되어 있다(Ivanova L.V., 1996; Numano., 1971). 또한, 에스트로겐을 콜레스테린 (cholesterin) 합성 저해제로 사용한 예도 보고되어 있다(Ekzoesterol, etinilestradiol, premarin; P.A. Nussbaumer, Hunkler F., 1967).In addition, it has been reported that cardiovascular susceptibility to atherosclerosis, which is a frequent occurrence in postmenopausal women, can be effectively reduced by increasing blood estrogen levels (Stout D.W., 1982). On the other hand, as a result of experiments on rabbits with atherosclerosis, it was confirmed that estrogen lowers blood lipid content and shows antiatherosclerotic effect (Ivanova L.V., 1996; Numano., 1971). In addition, examples of using estrogen as a cholesterin synthesis inhibitor have been reported (Ekzoesterol, etinilestradiol, premarin; P.A. Nussbaumer, Hunkler F., 1967).
합병증을 갖는 아테롬성 동맥경화증은 혈중 에스트로겐 농도의 감소와 난소 기능의 감소 또는 상실로 인해 폐경기의 여성에게서 발생 빈도가 높으며, 서구에서는 에스트로겐을 이용한 장기간에 걸친 호르몬요법이 광범위하게 이용되고 있고,많은 임상 연구결과들도 에스트로겐의 긍정적인 효과를 보고하고 있다(MyasnikovL.A., 1961; Kraznai I., 1963; Patrono V., 1972). 또한, 심장의 아테롬성 동맥경화증이 합병증으로 된 심근경색 질환을 가진 50~70세 남성의 치료에서도 상기와 같은 양호한 결과가 얻어졌음이 보고된 바 있다(Statut R.U., 1985).Atherosclerosis with complications is more common in postmenopausal women due to decreased blood estrogen levels and decreased or lost ovarian function, and long-term hormonal therapy with estrogen is widely used in the West, and many clinical studies The results also report the positive effects of estrogen (Myasnikov L.A., 1961; Kraznai I., 1963; Patrono V., 1972). In addition, it has been reported that the above good results have been obtained in the treatment of 50 to 70 year old males with myocardial infarction, which is a complication of atherosclerosis of the heart (Statut R.U., 1985).
또한, 에스트로겐은 자가면역 질환, 예컨대, 류마토이드 관절염 등에 대해 완화 효과를 갖는 것으로 알려져 있다(Chander & Spector; 50:139). 류마토이드 관절염과 같은 자가면역 질환은 세포매개성 면역 및 체액매개성 면역에 있어서의 이상 조절로 야기되며, 종종 자가 항원에 대한 비정상적이거나 또는 강화된 T 세포, B 세포 및 대식세포성 작동세포 기능과 관련되고, 자가 항원에 대한 이들 세포성 성분들의 활성은 자가 내성과 관련된 피드백 기작의 파괴와 관련되어 있는 것으로 여겨진다. 예컨대, 하시모토(Hashimoto) 갑상선염과 같은 자가면역 질환은 가임 연령인 여성에서 우세하며, 여성 대 남성의 발병 비율은 약 50:1 이다(Ahmed 등, 121:531(1985)).In addition, estrogen is known to have a palliative effect against autoimmune diseases such as rheumatoid arthritis (Chander &Spector; 50: 139). Autoimmune diseases such as rheumatoid arthritis are caused by abnormal control in cell-mediated and humoral-mediated immunity and are often associated with abnormal or enhanced T cell, B cell and macrophage effector function against autologous antigens. It is believed that the activity of these cellular components on autoantigens is associated with disruption of the feedback mechanism associated with self tolerance. For example, autoimmune diseases such as Hashimoto's thyroiditis prevail in women of childbearing age, with a female to male incidence of about 50: 1 (Ahmed et al., 121: 531 (1985)).
에스트로겐은 T 세포 기능에 대해서는 억제 역할을 하지만 B 세포에 대해서는 면역 자극 효과를 갖는 것으로 입증되었다. 따라서, 에스트로겐은 T 세포 기능의 저해를 통해, 류마토이드 관절염, 다경화증, 길랭-바레(Guillan-Barre)증후군, 하시모토 갑상선염을 포함하는 활성화된 T 세포와 관련된 질환의 예방 및 치료에 유용할 것으로 기대되고 있다(Holmadahl, J. 2:651 (1989)).Estrogens have been shown to have an inhibitory role on T cell function but have an immune stimulating effect on B cells. Thus, estrogen is expected to be useful for the prevention and treatment of diseases associated with activated T cells, including rheumatoid arthritis, polysclerosis, Guillan-Barre syndrome, Hashimoto's thyroiditis, through inhibition of T cell function. Holmadahl, J. 2: 651 (1989).
T 세포에 대한 에스트로겐의 억제 효과와 더불어, 에스트로겐은 자가 면역성질환에 대한 예방 역할도 하는 것으로 믿어지고 있다. 마루이(Marui, j. 92:1866 (1993))는 산화방지제가 VCAM-1의 내피 발현을 억제한다고 보고하고 있다. 즉, VCAM-1은 맥관계 외부, 혈관 주위 및 표적 기관 내로의 트래픽킹(trafficking)과 관련된 T 세포 및 대식세포의 인테그린(integrin)인 VLA4에 대한 리간드로서, 에스트로겐은 산화방지제이기 때문에 세포의 VLA-4 의존성 트래픽킹을 저해시키고 결과적으로 자가면역-매개성 질환과 관련된 면역의 연쇄증폭반응(cascade)을 방해하는 것으로 알려져 있다.In addition to the inhibitory effect of estrogen on T cells, estrogen is believed to play a protective role against autoimmune diseases. Marui, j. 92: 1866 (1993) reports that antioxidants inhibit endothelial expression of VCAM-1. In other words, VCAM-1 is a ligand for VLA4, an integrin of T cells and macrophages involved in trafficking outside the vascular system, around blood vessels and into target organs, and because estrogen is an antioxidant, 4 It is known to inhibit dependent trafficking and consequently to interfere with the cascade of immunity associated with autoimmune-mediated diseases.
또한, 에스트로겐은 대장암의 억제제인 것으로 보고되고 있다. 이와 관련한 코호트의 연구 결과는 에스트로겐 보충요법이 담즙산 합성에 의해 여성에서의 결장직장암의 위험을 감소시키는 것으로 보고하고 있다. 최근들어 서구에서의 여성결장직장암의 사망율 감소는 폐경 후 에스트로겐 보충요법이 광범위하게 사용된 결과인 것으로 믿어지고 있다(Mayer, Chapter 92, in , 14th ed., 1998).Estrogens are also reported to be inhibitors of colorectal cancer. Cohort's findings in this study suggest that estrogen supplementation reduces the risk of colorectal cancer in women by bile acid synthesis. Recently, the reduction in mortality in colorectal cancer in the West is believed to be the result of extensive use of postmenopausal estrogen supplementation (Mayer, Chapter 92, in, 14th ed., 1998).
상기한 사항 외에도, 에스트로겐은 생체 외 및 생체 내에서 내피 세포의 성장을 가속화하는 것으로 보고되어 있다(Morales, D.E., 91:755-63(1995); Krasinski, K., 95:1768-72(1997)). 에스트로겐은 혈관 상해 후 신속한 재내피세포증식 (reendothelialization)을 유도하며 이는 혈관내피성장인자의 국소적 발현 증가에 기인하는 것일 수 있다. 또한, 에스트로겐은 에스트로겐 수용체-의존 방식으로 배양된 인간내피세포의 고사를 저해한다(Spyridopoulos,I., J., 95:1505-14(1997)). 에스트로겐에 의한 내피 일체성 초기복원 현상은 산화질소의 이용가능성을 증가시킴으로써 상해에 대한 반응 감쇄를 초래하며, 평활근 세포의 증식을 직접 저해하는 것으로 보고되어 있다(Cornwell, T.L., J., 267:C1405-C1413(1994)).In addition to the above, estrogens have been reported to accelerate the growth of endothelial cells in vitro and in vivo (Morales, DE, 91: 755-63 (1995); Krasinski, K., 95: 1768-72 (1997). )). Estrogen induces rapid reendothelialization after vascular injury, which may be due to increased local expression of vascular endothelial growth factor. In addition, estrogens inhibit apoptosis of human endothelial cells cultured in an estrogen receptor-dependent manner (Spyridopoulos, I., J., 95: 1505-14 (1997)). Endothelial initiation by estrogen has been reported to decrease the response to injury by increasing the availability of nitric oxide and directly inhibit the proliferation of smooth muscle cells (Cornwell, TL, J., 267: C1405). -C1413 (1994).
또한, 에스트로겐은 역학적 증명에 의해 백내장에 대해 예방 효과가 있다고 제안되어 있다. 여성은 남성보다 백내장으로 발전될 위험이 더 높기는 하지만, 이런 위험도의 증가는 폐경후 에스트로겐이 감퇴되었을 때 발생하기 쉬운 것으로 알려져 있다(Livingston, P.M., J., 26:1-6, (1994); Klein, B.E., J., 116:219-225, (1998)). 544명의 여성을 피실험 대상으로 한 연구에서, 이른 시기의 폐경은 백내장으로의 발전 위험성을 약 2.9배 증가시키는 것으로 보고되어 있다(Shibata, T., J., 26:25-33, (1994)). 또한, 소규모 역학적 연구 결과에 따르면 폐경 후의 에스트로겐 보충요법이 백내장의 발병을 감소시키는 것으로 보고하고 있다(Klein., J., 112:85-91, (1994); Cumming, R.G. 및 Mitchell, P., J., 145:242-249, (1997); Benitez del Castillo, J.M., J., 104:970-973, (1997)). 연령과 관련된 백내장의 생체 내 랫(rat) 모델은 에스트로겐의 예방 효과가 게놈에 의한 것이라고 제안하고 있다(Bigsby, R.M., J,. 96:9328-9332, (1999)).In addition, estrogen has been suggested to have a prophylactic effect against cataracts by epidemiological proof. Although women are at higher risk of developing cataracts than men, this increased risk is known to occur when postmenopausal estrogens are reduced (Livingston, PM, J., 26: 1-6, (1994) Klein, BE, J., 116: 219-225, (1998). In a study of 544 women, early menopause reported a 2.9-fold increase in the risk of developing cataracts (Shibata, T., J., 26: 25-33, (1994) ). In addition, small-scale epidemiologic studies have reported that postmenopausal estrogen supplementation reduces the incidence of cataracts (Klein., J., 112: 85-91, (1994); Cumming, RG and Mitchell, P., J., 145: 242-249, (1997); Benitez del Castillo, JM, J., 104: 970-973, (1997)). In vivo rat models of age-related cataracts suggest that the prophylactic effect of estrogens is due to genomes (Bigsby, R.M., J ,. 96: 9328-9332, (1999)).
전술한 바와 같이, 에스트로겐은 여성의 비뇨생식계통 뿐만 아니라, 뼈조직, 심장, 혈관, 중추신경계, 피부 조직 등 다양한 조직의 기능을 보호하는 작용이 탁월하기 때문에, 현재 폐경기 증상에 대한 가장 효과적인 예방 및 치료 방법으로서는 호르몬 대체요법(hormone replacement therapy; HRT)이 널리 사용되어 오고 있으며(Lobo RA & Speroff L. FertilSteril 61: 592-595, 1994), 이는 폐경기 증상의 원인이 에스트로겐의 분비 감소에서 기인함에 착안하여 합성 에스트로겐, 또는 합성 에스트로겐과 합성 프로게스테론의 혼합물을 인위적으로 투여하는 방법이다.임상적으로는 무월경이나 월경이상의 치료, 월경의 인위적 이동, 갱년기장애, 전립선암이나 유방암에 대한 호르몬 요법, 골다공증 등에 대해 적용되고 있다. 또한, 경구피임약은 황체호르몬과 에스트로겐으로 이루어진다. 또한, 배란 유발제인 클롬펜이나 유방암 치료에 쓰이는 타목시펜은 비스테로이드성 항(抗)에스트로겐이다. 이러한 합성 에스트로겐 호르몬 제제의 투여는 정제 형태로 경구 투여하거나 피부에 접착시키는 패취형 또는 국소적 적용을 위한 크림제 등의 형태로 적용되고 있다.As described above, estrogen is excellent for protecting the functions of various tissues such as bone tissue, heart, blood vessels, central nervous system, skin tissue, as well as urogenital system of women. Hormone replacement therapy (HRT) has been widely used as a treatment method (Lobo RA & Speroff L. Fertil Steril 61: 592-595, 1994), which is attributed to the reduced estrogen secretion. It is a method for artificially administering a synthetic estrogen or a mixture of synthetic estrogen and synthetic progesterone. Is being applied. Oral contraceptives also consist of progesterone and estrogen. In addition, clomphene, an ovulatory inducer, and tamoxifen, which are used to treat breast cancer, are nonsteroidal antiestrogens. Administration of such synthetic estrogen hormone preparations has been applied in the form of oral administration in the form of tablets, or in the form of a patch for topical application or a cream for topical application.
그러나, 합성 에스트로겐의 장기간에 걸친 투여는 유방암과 자궁암을 유발할 수 있다는 심각한 문제점을 갖고 있는 것으로 많은 연구 결과는 보고하고 있다(예컨대, Hunt K etal, Br J Obstet Gynaecol 94:620-635, 1987; Ravnikar VA. Women's Health Issues 2:75-82, 1992). 최근 들어서는 장기간에 걸친 합성 에스트로겐 대체 요법이 유방암을 유발할 가능성이 높다는 믿을 만한 주장이 다수 제기되면서 학자들 간에는 물론, 사회 전반에 걸쳐 논란이 가열되고 있다. 아직 확실히 증명된 것은 아니지만, 합성 에스트로겐 대체 요법을 받는 여성에 있어서의 유방암 발생 위험은 시간 경과에 따른 에스트로겐 노출 용량과 관련이 있는 것으로 믿어지고 있다.However, many studies have reported that long-term administration of synthetic estrogens can lead to breast and uterine cancer (eg, Hunt K et al, Br J Obstet Gynaecol 94: 620-635, 1987; Ravnikar). VA.Women's Health Issues 2: 75-82, 1992). In recent years, controversy has been heating up among scholars and across society, with a number of credible claims that long-term synthetic estrogen replacement therapy is likely to cause breast cancer. Although not yet proven, it is believed that the risk of developing breast cancer in women receiving synthetic estrogen replacement therapy is associated with the dose of estrogen exposure over time.
따라서, 상기한 호르몬 대체 요법에 사용되는 합성 에스트로겐의 보다 안전한 대체물로서 식물성 에스트로겐인 피토에스트로겐(phytoestrogen)을 찾고자 하는 연구가 최근 활발히 진행되고 있는 추세에 있다.Therefore, there is a recent trend to actively search for phytoestrogen, which is a phytoestrogen, as a safer substitute for the synthetic estrogen used in the hormone replacement therapy.
상기한 피토에스트로겐은 동물의 체내에서 에스트로겐성 효과를 발휘하는 식물 중에 존재하는 비스테로이드성 화합물을 지칭하며, 항암 작용과 심장병에 효과가 있는 것으로 알려져 있는 곡물, 과일, 채소들의 대부분은 피토에스트로겐을 미량 포함하고 있으며, 특히 콩을 포함한 콩 가공식품(두유, 두부, 된장 등)과 각종 곡류나 과일류, 알팔파, 클로버 등에 상대적으로 많이 포함되어 있다. 이소플라본의 경우에는 주로 콩과 식물에, 리그난의 경우에는 주로 곡류에 많이 함유되어 있는 것으로 알려져 있다.The phytoestrogens described above refer to nonsteroidal compounds present in plants that exert an estrogenous effect in the body of animals, and most of the grains, fruits, and vegetables known to be effective against anticancer activity and heart disease contain trace amounts of phytoestrogens. In particular, it is relatively contained in soybean processed foods including soybeans (soy milk, tofu, miso, etc.) and various grains, fruits, alfalfa and clover. It is known that isoflavones are mainly contained in legumes, and lignans are mainly contained in cereals.
상기한 식물성 에스트로겐의 활성효과는 체내에서 생성되는 내인성 에스트로겐에 비해 1/100∼1/1000에 불과하지만, 그 함유량은 훨씬 크므로 결과적으로 충분한 에스트로겐 효과를 얻을 수 있다. 식물성 에스트로겐의 대표적인 활성으로는 골소실을 방지하고 골밀도를 증가시키는 효과와 폐경 여성에게 투여 시 FSH와 LH의 감소 및 폐경기 증상의 완화에 효과가 있다고 알려져 있으며, 이소플라본 중 하나인 제니스테인(genistein)은 세포의 단백질 타이로신 인산화효소(proteintyrosine kinase)를 억제하여 암세포의 성장을 억제하는 항암효과가 있음이 보고된 바 있다.The activating effect of the above-mentioned phytoestrogens is only 1/100 to 1/1000 of the endogenous estrogen produced in the body, but since the content is much larger, a sufficient estrogen effect can be obtained as a result. Representative activities of phytoestrogens are known to prevent bone loss, increase bone density, reduce FSH and LH when administered to postmenopausal women, and alleviate menopausal symptoms. Genistein, one of isoflavones, It has been reported that there is an anticancer effect of inhibiting the growth of cancer cells by inhibiting protein tyrosine kinase of the cells.
따라서, 폐경기 여성에서의 골다공증의 예방과 치료에 사용될 수 있음은 물론, LDL(low density lipid)을 낮추고 HDL(high density lipid)을 높이며, 자궁내막과 유방에서는 항암효과를 보이는 에스트로겐 작용제 또는 길항제로 역할을 함과 아울러, 피부 개선, 백내장 및 대장암 예방, 자가면역성 질환의 예방 등에 효과적이면서도 안전하게 사용할 수 있는, 폐경기 증상의 예방 및 치료를 위한 건강보조식품 또는 치료제로서 이용할 수 있는 효과적인 식물성 에스트로겐에 대한 요청이 급격히 증대되고 있다.Therefore, it can be used for the prevention and treatment of osteoporosis in postmenopausal women, lowers LDL (low density lipid) and high HDL (high density lipid), and acts as an estrogen agonist or antagonist with anticancer effect in endometrium and breast. In addition, there is a request for an effective phytoestrogens that can be used as a dietary supplement or therapeutic agent for the prevention and treatment of menopausal symptoms, which can be effectively and safely used for skin improvement, prevention of cataracts and colon cancer, and prevention of autoimmune diseases. This is increasing rapidly.
이러한 요청에 부응하여, 현재 식품 및 의약품 산업계에서는 천연자원 중에서 에스트로겐의 생리활성을 가지면서도, 유방암이나 자궁암 등을 유발하지 않음은 물론, 내분비계 장애 물질로서 작용하지 않는 안전한 천연호르몬 대체 식물을 찾고자 광범위한 노력을 지속하고 있다.In response to this request, the food and pharmaceutical industry is now seeking to find safe natural hormone replacement plants that have the physiological activity of estrogen in natural resources, do not cause breast cancer or uterine cancer, and do not act as endocrine disruptors. Efforts are ongoing.
따라서, 본 발명의 첫 번째 목적은 갱년기 또는 폐경기 여성에 있어서의 갱년기 또는 폐경기 증상을 효과적으로 예방 또는 치료할 수 있는 건강보조식품 또는 예방 및 치료용 조성물을 제공하기 위한 것이다.Accordingly, a first object of the present invention is to provide a dietary supplement or a composition for preventing or treating menopausal or menopausal women, which can effectively prevent or treat menopausal or menopausal symptoms.
본 발명의 두 번째 목적은 상기한 본 발명의 첫 번째 목적에 따른 건강보조식품 또는 예방 및 치료용 조성물의 제조방법을 제공하기 위한 것이다.A second object of the present invention is to provide a method for preparing a health supplement or a composition for preventing and treating according to the first object of the present invention.
이하, 본 발명에 관하여 상세히 설명하기로 한다.Hereinafter, the present invention will be described in detail.
본 발명은 갱년기 또는 폐경기 여성에 대한 천연 에스트로겐 공급원으로서의 석류 추출물을 포함하는 건강보조식품, 또는 갱년기 또는 폐경기 증후군의 예방 및 치료용 조성물과 그 제조방법에 관한 것이다.The present invention relates to a dietary supplement comprising a pomegranate extract as a natural estrogen source for menopausal or postmenopausal women, or a composition for the prophylaxis and treatment of menopausal or menopausal syndrome and a method for producing the same.
본 발명의 건강보조식품 또는 조성물의 제조에는 주원료로써 석류가 이용되며, 석류는 이란을 중심으로 한 아시아 서남부 및 인도 북서부의 자생 식물로서, 현재는 아열대 및 열대 각지에 널리 퍼져 있는 식물이다. 예로부터 석류, 특히 흑석류는 강장제로 알려져 왔으며 특히 고혈압과 동맥경화 예방에 좋은 효과를 나타내는 것으로 알려져 있다. 또한, 수용성 당질이 38~47%로 다량 포함되어 있으며,다양한 비타민과 미네랄을 포함한다.Pomegranate is used as a main ingredient in the manufacture of the dietary supplement or composition of the present invention, and the pomegranate is a native plant in southwestern Asia and northwestern India, centered on Iran, and is currently a plant widely spreading in subtropical and tropical regions. Pomegranate, especially black pomegranate, has been known as a tonic for a long time, and it is known to have a good effect on preventing hypertension and atherosclerosis. In addition, it contains a large amount of water-soluble sugars (38-47%), and contains a variety of vitamins and minerals.
본 발명에 있어 석류의 종류에는 특별한 제한은 없지만, 흑석류가 바람직하며, 구체적인 예로써는 이란산 흑석류를 들 수 있다.Although there is no special restriction | limiting in the kind of pomegranate in this invention, Black pomegranate is preferable, A specific example is Iranian black pomegranate.
본 발명자들에 의해 규명된 바에 의하면, 석류 농축물은 석류의 산지 및 수확 시기 등에 따라 약간의 차이는 있지만, 특히 흑석류 농축물은 피토에스트로겐을 상당량 포함하고 있으며, 구체적으로는 카테킨 1.0~2.0ppm, 다이드제인 20~30ppm, 제니스테인 0.1~0.5ppm, 쿠에르세틴 8.0~14.0ppm, 17β-에스트라디올 0.5~0.3ppm 및 2,3-디-MeO-에스트라디올 0.01~0.10ppm을 포함한다.According to the present inventors, pomegranate concentrate has a slight difference depending on the pomegranate origin and harvesting time, in particular, the black pomegranate concentrate contains a significant amount of phytoestrogens, specifically catechin 1.0 ~ 2.0ppm, 20 to 30 ppm of diyzedine, 0.1 to 0.5 ppm of genistein, 8.0 to 14.0 ppm of quercetin, 0.5 to 0.3 ppm of 17β-estradiol and 0.01 to 0.10 ppm of 2,3-di-MeO-estradiol.
본 발명의 제조방법에 따라 제조되는 석류 농축액은 수분 함량 35~42중량%, 지질 함량 0.3~0.6중량%, 단백질 함량 0.7~1.2중량%, 회분 1.2~1.6중량%, 탄수화물 38~47중량%를 포함한다. 본 발명에 있어서의 석류 농축액은 과육으로의 농축액, 과육과 씨앗의 농축액 및, 과피를 포함하는 원료로부터의 농축액을 포함하는 의미로 사용된다.Pomegranate concentrate prepared according to the production method of the present invention is 35 to 42% by weight, 0.3 to 0.6% by weight lipid, 0.7 to 1.2% by weight protein, 1.2 to 1.6% by weight ash, 38 to 47% by weight carbohydrate Include. The pomegranate concentrate in this invention is used by the meaning containing the concentrate to the flesh, the concentrate of the flesh and seeds, and the concentrate from the raw material containing a peel.
아미노산으로서는 트레오닌, 발린, 메티오닌, 이소류신, 류신, 페닐알라닌, 트립토판, 리신의 필수 아미노산 8종을 비롯하여 아스팔트산, 세린, 글루탐산, 프롤린, 글리신, 알라닌, 시스테인, 티로신, 히스티딘, 알지닌을 포함한다.Amino acids include eight essential amino acids of threonine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan, lysine, asphaltic acid, serine, glutamic acid, proline, glycine, alanine, cysteine, tyrosine, histidine, alginine.
또한, 수용성 비타민으로서는 티아민(비타민 B1), 리보플라빈(비타민 B2), 아스콜빈산(비타민 C), 니아신, 비타민 B6를 포함하며, 지방산으로서는 미리스틴산, 팔미트산, 스테아린산, 올레인산, 리놀레인산 등을 포함하고, 약산 성분으로서는글리콜산 및 초산을 약간 포함한다.The water-soluble vitamins include thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), ascorbic acid (vitamin C), niacin and vitamin B 6 , and the fatty acids include myristic acid, palmitic acid, stearic acid, oleic acid, Linoleic acid and the like, and the weak acid component includes glycolic acid and acetic acid slightly.
본 발명에 따른 피토에스트로겐 함유 건강보조식품은 조성물 전 중량 기준으로 상기한 석류 농축 과즙을 0.1~99중량% 포함하며, 바람직하게는 3~70중량%, 더욱 바람직하게는 5~50중량% 포함한다. 가장 바람직하게는, 정제 또는 과립 형태인 경우에는 35~45중량%이며, 액제 형태인 경우에는 5~15중량%이다.The phytoestrogens-containing dietary supplement according to the present invention contains 0.1 to 99% by weight of the pomegranate concentrate, based on the total weight of the composition, preferably 3 to 70% by weight, more preferably 5 to 50% by weight. . Most preferably, it is 35 to 45% by weight in the form of tablets or granules, and 5 to 15% by weight in the form of a liquid.
또한, 선택적으로, 본 발명에 따른 피토에스트로겐 함유 건강보조식품은 칡 및/또는 대두 유래의 피토에스트로겐인 이소플라본을 조성물 전 중량 기준으로 각각 0.1~5.0중량% 포함할 수도 있다.Further, optionally, the phytoestrogens-containing dietary supplement according to the present invention may each contain 0.1 to 5.0% by weight of isoflavone, which is a phytoestrogen derived from bovine and / or soybean, based on the total weight of the composition.
본 발명에 따른 피토에스트로겐 함유 건강보조식품은 엄격히 제한적인 것은 아니나, 피부 개선 및 뼈와 연골 조직의 활성화에 도움이 되는 키토올리고당 또는 연골 유래의 글루코오스아민을 0.1~8.0중량% 함유시킬 수도 있다.The phytoestrogens-containing dietary supplement according to the present invention is not strictly limited, but may contain 0.1 to 8.0% by weight of chitooligosaccharide or cartilage derived from cartilage, which is helpful for skin improvement and activation of bone and cartilage tissue.
또한, 필요에 따라 비타민 E, 비타민 C, 니코틴산아미드, 리보플라빈 등과 같은 비타민류를 0.01~4중량% 포함할 수도 있다.In addition, if necessary, vitamins such as vitamin E, vitamin C, nicotinic acid amide, riboflavin and the like may contain 0.01 to 4% by weight.
본 발명에 따른 피토에스트로겐 함유 건강보조식품이 정제나 과립제, 또는 캡슐제 등의 고형 제제 형태인 경우에는, 콜라겐 및/또는 뮤코다당을 포함시킬 수도 있으며, 이 경우 함유량은 전 조성물 중량 기준으로 각각 2.5~5.0중량% 및 5.0~10.0중량%의 범위이다.When the phytoestrogens-containing dietary supplement according to the present invention is in the form of a solid preparation such as tablets, granules, or capsules, collagen and / or mucopolysaccharide may be included, in which case the content is based on the total weight of the composition. It is the range of 2.5-5.0 weight% and 5.0-10.0 weight%.
본 발명에 따른 피토에스트로겐 함유 건강보조식품은 습식 조립법 또는 건식 조립법에 의해 롤러 컴팩터(Roller compactor)를 이용하는 컴팩팅법 또는 강타법 등에 의해 과립 또는 통상적인 정제 형태로 제형화된다.The phytoestrogens-containing dietary supplement according to the present invention is formulated in the form of granules or conventional tablets by a compacting method or a crushing method using a roller compactor by a wet granulation method or a dry granulation method.
통상적으로, 정제의 제조에 있어서 주성분 이외의 첨가물은 모두 첨가제 또는 부형제라 통칭되며, 보다 자세하게 분류하면, 부형제, 결합제, 붕해제, 활택제 등으로 나눌 수 있다.In general, in the manufacture of tablets, all additives other than the main component are collectively referred to as additives or excipients, and in more detail, may be divided into excipients, binders, disintegrants, lubricants and the like.
부형제는 정제에 관한 경험, 비용, 주성분과의 적합성 등을 고려하여 선택되며, 보통 정제에 일정한 부피를 주고 타정성을 좋게 할 목적으로 사용된다. 적합한 부형제의 예로서는, 유당, 라올린(Raolin), 만니톨, 전분, 분말 백당, 인산칼슘, 미결정 셀룰로오스, 콜로이드성 실리카 등을 들 수 있으나, 본 발명에 있어서 특히 바람직한 부형제로서는 유당을 들 수 있으며, 그 함량은 전 조성물 중량 기준으로 10~25중량%의 범위이다.Excipients are selected in consideration of tablet experience, cost, compatibility with the main ingredient, etc., and are usually used for the purpose of giving a tablet a certain volume and good tabletting ability. Examples of suitable excipients include lactose, raolin, mannitol, starch, powdered white sugar, calcium phosphate, microcrystalline cellulose, colloidal silica and the like, but particularly preferred excipients in the present invention include lactose. The content is in the range of 10-25% by weight, based on the total weight of the composition.
결합제는 과립 상호간의 부착성을 향상시키는 외에, 압축된 다음 정제의 형태를 유지하는 작용을 한다. 결합제의 양은 가하는 사람의 경험, 다른 성분의 성질 등에 따라 결정되며, 그 양이 너무 적으면 결합능이 부족하게 되고 너무 많으면 지나치게 굳어지게 되므로 정제의 붕해 및 용출 속도가 늦어지게 된다. 바람직한 결합제의 종류 및 첨가량에 대하여 언급하면, 옥수수 전분 현탁액, 포도당 용액, 말토오스, 천연 검(gum), 셀룰로오스 유도체(메틸셀룰로오스, 카르복시메틸셀룰로오스, 미결정셀룰로오스), 젤라틴, 포비돈, 콜라겐, 뮤코다당 등을 들 수 있으며, 본 발명에 있어서 바람직한 결합제로서는 피부 개선 효과 및 연골 강화 효능이 있는 콜라겐 또는 뮤코다당이며, 그 비율은 전술한 바와 같다.In addition to improving adhesion between the granules, the binder acts to maintain the shape of the tablet after being compressed. The amount of the binder is determined according to the experience of the person to be added, the nature of the other ingredients, etc. If the amount is too small, the binding capacity is insufficient, if too large it will become too hard to slow down the disintegration and dissolution rate of the tablet. Referring to the type and amount of the preferred binder, corn starch suspension, glucose solution, maltose, natural gum, cellulose derivatives (methylcellulose, carboxymethylcellulose, microcrystalline cellulose), gelatin, povidone, collagen, mucopolysaccharide, etc. Preferred binders in the present invention include collagen or mucopolysaccharide having a skin improving effect and cartilage strengthening effect, and the ratio thereof is as described above.
활택제는 호퍼로부터 타정기의 다이(die)로의 유동 개선, 펀치나 다이에의 부착 방지, 타정기에서 정제를 인출할 때의 저항 감소, 정제에의 광택 부여 등과같은 효과를 가져온다. 바람직한 활택제의 예로서는, 탈크, 마그네슘 스테아레이트, 스테아린산, 칼슘 스테아레이트, 발연 실리콘 이산화물 등을 들 수 있다. 특히 바람직한 활택제로는 썬 액티브철 및 알긴산 나트륨을 들 수 있고, 활택제의 양이 너무 많아지면 정제의 붕해와 용출을 지연시키므로, 본 발명에 있어서는 적어도 1종의 상기한 활택제를 총 정제함량에 대하여 0.1~0.5중량%의 비율로 사용하는 것이 좋다.Glidants have effects such as improved flow from the hopper to the die, prevention of adhesion to punches or dies, reduced resistance when taking tablets out of the tablet press, glossing of the tablets, and the like. Examples of preferred lubricants include talc, magnesium stearate, stearic acid, calcium stearate, fumed silicon dioxide, and the like. Particularly preferred glidants include sun-activated iron and sodium alginate, and if the amount of the glidant is too high, the disintegration and elution of the tablets is delayed. In the present invention, at least one of the glidants is added to the total tablet content. It is good to use in the ratio of 0.1 to 0.5 weight% with respect to.
붕해제는 수분과 접촉시 팽창하여 위장관 내에서 정제를 붕괴시키는 효과를 가져오며, 바람직한 붕해제의 예로서는 앞서 결합제 및 부형제로서 언급한 것들을 들 수 있다.Disintegrants have the effect of swelling upon contact with moisture to disrupt tablets in the gastrointestinal tract, and examples of preferred disintegrants include those mentioned above as binders and excipients.
부형제, 결합제 및 붕해제는 일반적으로 성분 간의 상호 관계 등을 고려하여 적절히 조합되며, 결합제로서의 목적으로 첨가한 것이 다른 부형제와의 상호 작용에 의하여 오히려 붕해제로서의 작용을 하는 경우도 있고, 그 반대의 경우도 있으므로 이들 간의 엄격한 구별은 절대적인 것이 아니며, 오히려 상대적이다.Excipients, binders and disintegrants are generally appropriately combined in consideration of the interrelationships between components, and the like may be added as a binder to act as a disintegrant by interaction with other excipients, and vice versa. In some cases, the strict distinction between them is not absolute, but rather relative.
상기한 정제나 과립, 캡슐제의 고형 제제 형태인 경우에는 석류 농축 과즙의 중량 기준으로 500mg, 750mg, 1000mg 제형으로 제조할 수 있으며, 750mg 제형의 경우에는 1일 6~12개의 정제를 경구 섭취한다.In the case of the tablets, granules, and capsules in the form of solid preparations, the pomegranate concentrate can be prepared in 500 mg, 750 mg, or 1000 mg formulations based on the weight of the concentrated fruit juice. .
한편, 본 발명에 따른 피토에스트로겐 함유 건강보조식품이 액제 형태인 경우에는, 안정화된 교질 용액을 형성시키기 위하여 폴리덱스트로오스를 전 조성물 중량 기준으로 3~10중량% 첨가하는 것이 바람직하다.On the other hand, when the phytoestrogens-containing dietary supplement according to the present invention is in the form of a liquid, it is preferable to add 3 to 10% by weight of polydextrose based on the total weight of the composition in order to form a stabilized colloidal solution.
글루코오스아민과 전술한 비타민류를 전술한 바와 같은 양으로 포함시킬 수있음은 물론이다.Of course, glucose amine and the aforementioned vitamins can be included in the amounts described above.
그 외 나머지 잔부는 대부분 정제수이다.The rest of the rest is mostly purified water.
상기한 액제 형태인 경우에는 50㎖ 또는 100㎖ 용량으로 진공 포장한 ??을 1일 1~2포 경구 섭취할 수 있다.In the case of the above-described liquid form, vacuum packed in a 50ml or 100ml dose of ?? can be taken orally 1 to 2 bags per day.
이하, 본 발명에 따른 피토에스트로겐 함유 건강보조식품의 제조방법에 대하여 설명하기로 한다.Hereinafter, a method for preparing a phytoestrogens-containing health supplement according to the present invention will be described.
먼저, 액액 분리에 의한 용매 추출법에 의한 제조 단계는 다음과 같다.First, the manufacturing step by the solvent extraction method by liquid liquid separation is as follows.
(A) 분쇄한 석류에 물, 메탄올, 에탄올, n-헥산, 에틸아세테이트, 또는 이들의 임의의 혼합물을 가하는 용매 혼합 단계(A) a solvent mixing step of adding water, methanol, ethanol, n-hexane, ethyl acetate, or any mixture thereof to the pulverized pomegranate
(B) 용매 종류에 따라 60~100℃의 온도 조건 하에 0.5~2시간 동안 환류시키는 환류 단계(B) reflux step for 0.5 to 2 hours under a temperature condition of 60 ~ 100 ℃ depending on the solvent type
(C) 상층 분리 단계(C) upper separation step
(D) 용매 제거 단계(D) solvent removal step
추출 용매에 특별한 제한은 없으며, 바람직한 것은 메탄올 및 에탄올이며, 필요하다면 n-헥산 및/또는 에틸아세테이트 등을 첨가할 수도 있다.There is no particular limitation on the extraction solvent, preferred is methanol and ethanol, and n-hexane and / or ethyl acetate may be added if necessary.
상기한 환류 단계와 상층 분리 단계는 2~3회 반복하는 것이 바람직하다.The reflux step and the phase separation step are preferably repeated two to three times.
상기한 용매 제거 단계를 경유한 농축액은 약 30% 농축액으로서, 총 에스트로겐 함량은 약 1300~1700pg/㎖이다.The concentrate via the solvent removal step is about 30% concentrate, with a total estrogen content of about 1300-1700 pg / ml.
다음으로, 염산 처리에 의한 용매 추출법에 의한 제조 단계는 다음과 같다.Next, the manufacturing step by the solvent extraction method by hydrochloric acid treatment is as follows.
(A) 건조시켜 미분쇄한 석류에 물, 메탄올, 에탄올, n-헥산, 에틸아세테이트, 또는 이들의 임의의 혼합물을 가하는 용매 혼합 단계(A) a solvent mixing step of adding water, methanol, ethanol, n-hexane, ethyl acetate, or any mixture thereof to the dried and pulverized pomegranate
(B) 0.5~2시간 동안 환류시키는 환류 단계(B) reflux step for 0.5-2 hours
(C) 상층 분리 단계(C) upper separation step
(D) HCl 첨가 단계(D) HCl addition step
(E) 교반 단계(E) stirring step
(F) 글래스 필터 여과 단계(F) glass filter filtration step
(G) HCl 첨가 후 1~3시간 동안 60~100℃의 열수조에 정치하는 정치 단계(G) a stationary step of standing in a hot water bath at 60 to 100 ° C. for 1 to 3 hours after adding HCl.
(H) 냉각 단계(H) cooling stage
(I) 아세토니트릴 첨가 단계(I) acetonitrile addition step
(J) 용매 제거 단계(J) solvent removal step
상기한 환류 단계와 상층 분리 단계는 2~3회 반복하는 것이 바람직하다. HCl 은 0.1~1.0M 농도를 사용하고 균질하게 되도록 철저히 교반한 후 글래스 필터를 사용하여 과피, 과육 및/또는 씨앗의 미세 분쇄 입자를 제거하고 열수조에 정치하는 것에 의해서, 황산 또는 글루큐론산과의 포합 형태로 존재하는 에스트로겐을 비포합 형태의 에스트로겐으로 가수분해하게 된다. 이어서, 아세토니트릴을 첨가하여 세포내 성분들을 추출하고, 용매를 감압 증류법 등을 이용하여 제거한다.The reflux step and the phase separation step are preferably repeated two to three times. HCl is combined with sulfuric acid or glucuronic acid by using 0.1 ~ 1.0M concentration and stirring thoroughly to make it homogeneous, then using a glass filter to remove fine pulverized particles of skin, pulp and / or seeds and standing in a hot water bath. Estrogens present in the form are hydrolyzed to non-conjugated estrogens. Subsequently, acetonitrile is added to extract intracellular components, and the solvent is removed using distillation under reduced pressure or the like.
상기한 용매 제거 단계를 경유한 농축액은 약 40% 농축액으로서, 총 에스트로겐 함량은 약 1420~1830pg/㎖이다.The concentrate via the solvent removal step is about 40% concentrate with a total estrogen content of about 1420-1830 pg / ml.
상기한 아세토니트릴 첨가 단계에 이어서, (K) 37℃에서의 효소가수분해 단계, (L) 에틸아세테이트 첨가 추출 단계(바람직하게는 2~3회 반복 수행)를 수행한후, 최종적으로 (M) 용매 제거 단계를 수행할 수도 있다.Following the acetonitrile addition step described above, after (K) enzymatic hydrolysis step at 37 ° C., (L) ethyl acetate addition extraction step (preferably repeated 2-3 times), and finally (M) Solvent removal may also be performed.
에스트로겐은 많은 경우 황산 또는 글루큐론산과의 포합 형태로 존재하므로 비포합 형태의 에스트로겐으로 만들기 위하여 상기한 HCl에 의한 가수분해 외에 효소가수분해 단계를 독립적으로 또는 병행하여 수행할 수 있으며, 여기서의 효소가수분해단계는 0.2M의 초산과 초산 나트륨으로 pH 5.2로 맞춘 초산완충용액을 첨가한 후,Helix pomatia유래의 글루큐로니다제/아릴설파타제(독일, Boehringer Mannheim사 제)를 첨가하여 수행된다.In many cases, estrogen is present in the form of a conjugate with sulfuric acid or glucuronic acid, so that the enzymatic hydrolysis step may be performed independently or in addition to the hydrolysis by HCl to make an estrogen in a non-conjugated form. The decomposition step is performed by adding an acetate buffer solution adjusted to pH 5.2 with 0.2 M acetic acid and sodium acetate, followed by the addition of glucuronidase / arylsulfatase derived from Helix pomatia (manufactured by Boehringer Mannheim, Germany).
이 경우의 농축액은 약 50% 농축액으로서, 총 에스트로겐 함량은 약 1540~1980pg/㎖이다.The concentrate in this case is about 50% concentrate, with a total estrogen content of about 1540-1980 pg / ml.
이어서, 고상 추출법에 의한 제조방법에 대하여 설명하면 하기의 단계로 구성된다.Next, the manufacturing method by the solid phase extraction method is comprised of the following steps.
(A) 건조시켜 미분쇄한 석류에 물, 메탄올, 에탄올, n-헥산, 에틸아세테이트, 또는 이들의 임의의 혼합물을 가하는 용매 혼합 단계(A) a solvent mixing step of adding water, methanol, ethanol, n-hexane, ethyl acetate, or any mixture thereof to the dried and pulverized pomegranate
(B) 0.5~2시간 동안 환류시키는 환류 단계(B) reflux step for 0.5-2 hours
(C) 상층 분리 단계(C) upper separation step
(D) Sedolit AD-2 이온교환수지 통과 단계(D) Sedolit AD-2 ion exchange resin pass step
(E) 농축 단계(E) concentration step
(F) 전술한 바와 같은 37℃에서의 효소가수분해 단계(F) enzymatic hydrolysis step at 37 ° C. as described above
(G) 초산에틸 첨가 추출 단계(G) ethyl acetate addition extraction step
(H) 용매 제거 단계(H) solvent removal step
상기한 (B) 및 (C)의 단계와, (G)의 단계는 2~3회 반복하는 것이 바람직할 수 있다. (D) 단계에서의 컬럼 통과액은 별도로 모아 보관하고, 아세톤:메탄올(1:9 농도 구배) 용액을 이용한 용출액은 (D)~(G) 단계를 수행한 후, (D) 단계에서의 컬럼 통과액과 합하여 (H)의 용매 제거 단계를 수행한다.It may be preferable to repeat the steps of (B) and (C) and the step of (G) 2-3 times. The column pass-through solution in step (D) is collected and stored separately, and the eluate using an acetone: methanol (1: 9 concentration gradient) solution is performed after steps (D) to (G), and then the column in step (D). Combine with the pass-through to perform the solvent removal step of (H).
이 경우의 농축액은 약 50% 농축액으로서, 총 에스트로겐 함량은 약 1560~1960pg/㎖이다.The concentrate in this case is about 50% concentrate with a total estrogen content of about 1560-1960 pg / ml.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 하나, 이는 본 발명을 예증하기 위한 것일 뿐, 본 발명을 제한하고자 하는 것이 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, which are intended only to illustrate the present invention and are not intended to limit the present invention.
실시예 1: 흑석류 농축물의 제조Example 1 Preparation of Black Pomegranate Concentrate
수확 후 3개월 된 이란산 흑석류의 과육 1㎏을 분쇄한 다음, 에틸알코올 8ℓ를 붓고 1시간 동안 70℃의 온도에서 환류하였다. 환류 후 상층을 분리하였다. 나머지를 다시 동일한 조건 하에 환류하였으며 환류 후 상층을 분리한 다음, 모아진 상층을 합하였다. 상기한 상층을 65℃의 온도에서 회전 감압 증발기를 이용하여 용매를 제거하였다.After harvesting, 1 kg of iranian black stone flesh 3 kg after harvesting was pulverized, 8 liters of ethyl alcohol was poured and refluxed at a temperature of 70 ° C. for 1 hour. The upper layer was separated after reflux. The remainder was again refluxed under the same conditions and after the reflux the upper layer was separated and the combined upper layers were combined. The solvent was removed from the upper layer using a rotary vacuum evaporator at a temperature of 65 ° C.
결과로서 점조성 잔사를 214g 수득하였다.As a result, 214 g of a viscous residue was obtained.
실시예 2 : 흑석류 농축물의 제조Example 2 Preparation of Black Pomegranate Concentrate
수확 후 3개월 된 이란산 흑석류(과육+씨앗) 1㎏을 분쇄한 다음, 메틸알코올 9ℓ를 붓고 1시간 동안 60℃의 온도에서 환류하였다. 환류 후 상층을 분리하였다. 나머지를 다시 동일한 조건 하에 환류하였으며 환류 후 상층을 분리한 다음, 모아진 상층을 합하였다. 모아진 상층에 0.5M HCl을 100㎖을 첨가한 다음, 30분간 교반한 후, 글래스 필터를 통하여 여과하였다.After harvesting, 1 kg of Iranian black stone (pulp + seed) 3 months after harvesting was ground, 9 liters of methyl alcohol was poured and refluxed at a temperature of 60 ° C. for 1 hour. The upper layer was separated after reflux. The remainder was again refluxed under the same conditions and after the reflux the upper layer was separated and the combined upper layers were combined. 100 ml of 0.5 M HCl was added to the combined upper layers, followed by stirring for 30 minutes, followed by filtration through a glass filter.
여액에 다시 0.5M HCl을 100㎖을 첨가한 다음, 2시간 동안 65℃의 열수조에 정치한 후, 실온으로 냉각하였다. 이어서, 아세토니트릴 100㎖을 첨가한 다음, 70℃의 온도에서 회전 감압 증발기를 이용하여 용매를 제거하였다.100 ml of 0.5 M HCl was further added to the filtrate, and it was allowed to stand in a hot water bath at 65 DEG C for 2 hours, and then cooled to room temperature. Then 100 ml of acetonitrile were added and then the solvent was removed using a rotary vacuum evaporator at a temperature of 70 ° C.
결과로서 점조성 잔사를 267g 수득하였다.As a result, 267 g of a viscous residue was obtained.
실시예 3 : 흑석류 농축물의 제조Example 3 Preparation of Black Pomegranate Concentrate
실시예 2에서 얻은 잔사 100g에 0.2M 초산완충용액(pH 5.2)을 200㎖을 첨가한 후,Helix pomatia의 글루큐로니다제/아릴설파타제(독일, Boehringer Mannheim사 제)(글루큐로니다제 5.5U/㎖(38℃); 아릴설파타제 2.6U/㎖(38℃))를 50μL의 양으로 첨가하여 37℃에서 에스트로겐 포합체를 가수분해하였다. 이어서, 에틸아세테이트 100㎖를 첨가하고 2회 반복 추출하였다. 그 후, 80℃의 온도에서 회전 감압 증발기를 이용하여 용매를 제거하였다.After adding 200 ml of 0.2 M acetic acid buffer solution (pH 5.2) to 100 g of the residue obtained in Example 2, glucuronidase / arylsulfatase of Helix pomatia (manufactured by Boehringer Mannheim, Germany) (glucuronida) The estrogen conjugate was hydrolyzed at 37 ° C. by adding 5.5 U / ml (38 ° C.); arylsulfatase 2.6 U / ml (38 ° C.) in an amount of 50 μL. Then, 100 ml of ethyl acetate was added and extracted twice. Thereafter, the solvent was removed using a rotary vacuum evaporator at a temperature of 80 ° C.
결과로서 점조성 잔사 87g을 수득하였다.As a result, 87 g of a viscous residue was obtained.
실시예 4 : 흑석류 농축물의 제조Example 4 Preparation of Black Pomegranate Concentrate
수확 후 3개월 된 이란산 흑석류(과육+씨앗+과피) 1㎏을 분쇄한 다음, 메틸알코올 4ℓ과 N-헥산 2ℓ 및 물 4ℓ의 혼합 용매를 붓고 1시간 동안 85℃의 온도에서 환류하였다. 환류 후 상층을 분리하였다. 나머지를 다시 동일한 조건 하에 환류하였으며 환류 후 상층을 분리한 다음, 모아진 상층을 합하였다.After harvesting, 1 kg of Iranian black stone (pulp + seed + pepper) three months after harvesting was ground, 4 L of methyl alcohol, 2 L of N-hexane, and 4 L of water were poured and refluxed at a temperature of 85 ° C. for 1 hour. The upper layer was separated after reflux. The remainder was again refluxed under the same conditions and after the reflux the upper layer was separated and the combined upper layers were combined.
모은 상층을 입자 크기 0.1~0.2mm의 이온교환수지 Serdolit AD-2 수지 컬럼(아세톤/메탄올/증류수를 이용하여 차례로 환류 정제한 다음 증류수에 보관)에 장전하고 Bradlow. H.L. Steroids, 1977, 30, 581에 기재된 방법에 따라 컬럼을 통과시키고 통과액은 별도로 모아두었다. 다시 컬럼을 아세톤:메탄올 1:9의 농도 구배를 가는 용액으로 용출시킨 다음, 용출액을 65℃의 온도에서 회전 감압 증발기를 이용하여 농축하였다.The combined upper layers were loaded into an ion exchange resin Serdolit AD-2 resin column (particles of acetone / methanol / distilled water, then purified by reflux with acetone / methanol / distilled water) and stored in distilled water. H.L. The column was passed according to the method described in Steroids, 1977, 30, 581 and the flow through was collected separately. The column was again eluted with a solution having a concentration gradient of acetone: methanol 1: 9, and then the eluate was concentrated using a rotary vacuum evaporator at a temperature of 65 ° C.
농축 용액에 0.2M 초산완충용액(pH 5.2)을 300㎖을 첨가한 후, 글루큐로니다제/아릴설파타제를 첨가하여 37℃에서 2시간 동안 에스트로겐 포합체를 가수분해하였다. 이어서, 에틸아세테이트 200㎖를 첨가하고 2회 반복 추출하였다.300 ml of 0.2 M acetic acid buffer solution (pH 5.2) was added to the concentrated solution, followed by addition of glucuronidase / arylsulfatase to hydrolyze the estrogen conjugate for 2 hours at 37 ° C. Then 200 ml of ethyl acetate was added and extracted twice.
그 후, 상기한 추출액과 컬럼 통과액을 합하고 85℃의 온도에서 회전 감압 증발기를 이용하여 용매를 제거하였다.Thereafter, the extract and the column passing solution were combined and the solvent was removed using a rotary vacuum evaporator at a temperature of 85 ° C.
결과로서 점조성 잔사 135g을 수득하였다.As a result, 135 g of a viscous residue was obtained.
실시예 5 : 정제의 제조Example 5: Preparation of Tablets
실시예 4에서 얻은 농축물을 이용하여 하기와 같은 배합비(중량%)로 제형화한 정제를 제조하였다:Using the concentrate obtained in Example 4, a tablet formulated at the following compounding ratio (wt%) was prepared:
흑석류 농축물 40.0Black Pomegranate Concentrate 40.0
글루코오스아민 5.0Glucoseamine 5.0
콜라겐 3.5Collagen 3.5
뮤코다당 7.5Mucodose 7.5
비타민 E(분체) 2.5Vitamin E (powder) 2.5
리보플라빈 0.5Riboflavin 0.5
알긴산나트륨 0.3Sodium Alginate 0.3
썬 액티브철 0.2Sun Active Iron 0.2
유당 20.0Lactose 20.0
이소플라본(칡) 2.5Isoflavones 2.5
카르복시메틸셀룰로오스 15.0Carboxymethylcellulose 15.0
포도당 3.3Glucose 3.3
------------------------------------------------------------------------
100.0100.0
실시예 6 : 액제의 제조Example 6 Preparation of Liquid
실시예 1에서 얻은 농축물을 이용하여 하기와 같은 배합비(중량%)로 제형화한 50㎖ 용량의 액제를 제조하였다:The concentrate obtained in Example 1 was used to prepare a 50 ml dose of the formulation formulated in the following blending ratios (wt%):
흑석류 농축물 10.0Black Pomegranate Concentrate 10.0
글루코오스아민 0.7Glucoseamine 0.7
폴리덱스트로오스 6.3Polydextrose 6.3
비타민 C 0.1Vitamin C 0.1
솔비톨 1.0Sorbitol 1.0
니코틴산아미드 0.01Nicotinic Acid 0.01
정제수 잔부Purified water balance
--------------------------------------------------------------------
100.0100.0
실시예 7 : 일반성분분석Example 7: General Component Analysis
실시예 1에서 얻은 흑석류 농축물과 실시예 5의 정제에 대한 일반성분분석을 수행하였다.General ingredient analysis was performed on the black pomegranate concentrate obtained in Example 1 and the purification of Example 5.
시료의 수분함량은 105℃ 상압 가열 건조법, 조지방 함량은 속시렛추출법(Auto Soxtec System HT 1043, Tecator, Sweden), 조단백질 함량은 킬달법(Kjeltec 1030 Auto Analyzer, Tecator, Sweden)으로 측정된 질소량에 질소계수 6.25를 곱하여 산출하였으며, 조섬유의 함량은 H2SO4-NaOH 분해법으로(Dosi-Fiver 6 units, J.P. Selecta, Spain), 조회분은 직접회화법으로 측정하였다. 당질의 함량은 100%에서 단백질, 지방, 섬유질 및 회분의 양을 뺀 값으로 나타내었다.Moisture content of the sample was 105 ℃ atmospheric pressure drying, crude fat content was Soxhlet extraction method (Auto Soxtec System HT 1043, Tecator, Sweden), crude protein content was measured by Kjeltec 1030 Auto Analyzer, Tecator, Sweden. It was calculated by multiplying the coefficient by 6.25, and the content of crude fiber was measured by H2SO4-NaOH decomposition (Dosi-Fiver 6 units, JP Selecta, Spain), and crude ash was measured by direct ashing. Carbohydrate content is expressed as 100% minus the amount of protein, fat, fiber and ash.
그 결과를 하기의 표 1에 나타낸다.The results are shown in Table 1 below.
실시예 8 : 아미노산 분석Example 8 Amino Acid Analysis
실시예 3에서 얻은 흑석류 농축물과 실시예 5의 정제에 대하여 아미노산 분석을 수행하였다.Amino acid analysis was performed on the black pomegranate concentrate obtained in Example 3 and the purification of Example 5.
시료 1g을 6N HCl 20㎖과 함께 분해용 시험관에서 105℃에서 24시간 산가수분해시켜 얻은 분해액을 0.2㎛의 필터에서 여과한 후 닌하이드린법을 이용한 아미노산 자동분석기에서 분석하였다. 분석 기기는 6300 아미노산 분석기(Beckmann Inc., Fullerton, CA, USA)를 사용하였고, 검출은 460nm와 530nm에서 하였다. 사용한 컬럼은 소디움 컬럼(4.6mmx15cm)이었다.The digestion solution obtained by acid hydrolysis of 1 g of the sample with 20 ml of 6N HCl in a test tube for 24 hours at 105 ° C. was filtered through a 0.2 μm filter and analyzed by an amino acid autoanalyzer using the ninhydrin method. The analytical instrument used a 6300 amino acid analyzer (Beckmann Inc., Fullerton, Calif., USA) and detection was at 460 nm and 530 nm. The column used was a sodium column (4.6 mm x 15 cm).
그 결과를 하기의 표 2에 나타낸다(단위는 ppm).The results are shown in Table 2 below (unit is ppm).
실시예 9 : 무기질 및 약산 분석Example 9 Mineral and Weak Acid Analysis
실시예 4에서 얻은 흑석류 농축물과 실시예 5의 정제에 대하여 무기질 분석을 수행하였다.Mineral analysis was performed on the black pomegranate concentrate obtained in Example 4 and the purification of Example 5.
무기질 전처리는 건식법으로 하였으며 inductively coupled plasma-atomic emission spectrophotometer(Spectro flame Modula E, Fitchburg, MA, USA)용을 사용하였다. 기기 작동 조건은 다음과 같다.Mineral pretreatment was performed by dry method and used for inductively coupled plasma-atomic emission spectrophotometer (Spectro flame Modula E, Fitchburg, MA, USA). The instrument operating conditions are as follows:
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전력 수용상에 대한 1.2Kw1.2Kw for power reception
분무기 압력 메인하드 타입 C에 대한 3.5bar3.5bar for atomizer pressure mainhard type C
에어로솔 유속 0.3ℓ/minAerosol Flow Rate 0.3ℓ / min
시쓰(sheath) 기체류 0.3ℓ/minSheath gas flow 0.3ℓ / min
냉각 기체류 12ℓ/mimCooling gas flow 12ℓ / mim
파장(nm) Fe 275.574Wavelength (nm) Fe 275.574
Cu 324.754Cu 324.754
K 766.491K 766.491
Zn 213.856Zn 213.856
Mn 257.610Mn 257.610
P 178.290P 178.290
Na 588.995Na 588.995
Ca 373.690Ca 373.690
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결과를 하기의 표 3에 나타낸다(단위는 ppm).The results are shown in Table 3 below (unit is ppm).
실시예 10 : 비타민 분석Example 10 Vitamin Analysis
실시예 4에서 얻은 흑석류 농축물과 실시예 5의 정제에 대하여 비타민 분석을 수행하였다.Vitamin analysis was performed on the black pomegranate concentrate obtained in Example 4 and the tablets of Example 5.
비타민 A와 E는 클로로포름/물의 혼합 용매로 추출하여 HPLC로 분석하였다. 컬럼은 μ-Bondapak C18(4.6mmx15cm), 용매는 100% 메탄올로 용매의 이동속도는 분당 1㎖씩 흘려 주었으며, 검출은 비타민 A는 325nm에서 C는 295nm에서 하였다. 비타민 C는 5% 메타포스포인산 용액으로 신속히 추출하여 HPLC법으로 μ-Bondapak C18(4.6mm 내경x15cm), 용매는 100% H2O로 용매의 이동속도는 분당 1㎖씩 흘려주었으며 검출은 270nm에서 하였다. 다른 수용성 비타민들은 메탄올과 물의 1:1 혼합용매로 추출후 HPLC법으로 μ-Bondapak C18(4.6mmx15cm)의 컬럼에서, 100% H2O에서60% 메탄올의 용매로 20분간에 걸쳐 농도 구배를 걸어 주었으며, 분당 1㎖씩 흘려 주었고 검출은 270nm에서 하였다.Vitamins A and E were extracted with a mixed solvent of chloroform / water and analyzed by HPLC. The column was μ-Bondapak C18 (4.6mmx15cm), the solvent was 100% methanol, and the moving speed of the solvent was 1 ml / min. Detection was made at 325 nm for vitamin A and 295 nm for C. Vitamin C was rapidly extracted with 5% metaphosphophosphate solution, and the HPLC method was μ-Bondapak C18 (4.6mm inner diameter x 15cm), the solvent was 100% H2O, and the solvent flow rate was 1 ml per minute and detection was performed at 270 nm. The other water-soluble vitamins were extracted with a 1: 1 mixed solvent of methanol and water, and then gradientd over 20 minutes in a column of μ-Bondapak C18 (4.6 mmx15 cm) using a solvent of 100% H2O to 60% methanol. 1 ml per minute was passed and detection was performed at 270 nm.
결과를 하기의 표 4에 나타낸다(단위는 mg/100g).The results are shown in Table 4 below (unit: mg / 100g).
실시예 11 : 지방산 분석Example 11 Fatty Acid Analysis
실시예 2에서 얻은 흑석류 농축물과 실시예 5의 정제에 대하여 지방산 분석을 수행하였다.Fatty acid analysis was performed on the black pomegranate concentrate obtained in Example 2 and the purification of Example 5.
지방산 조성의 분석은 Bligh와 Byer법에 준하여 지질을 추출하고, n-헥산층을 메틸에스터화시킨 후 무수 Na2SO4로 탈수한 후 여과하여 GC로 분석하였다. 분석시 GC는 Hewlett Packard 6890A(Palo Alto, CA, USA)를 사용하였으며, 컬럼은 HP사 FFAP으로 주입 포트는 260℃, 검출 포트는 270℃, 오븐은 초기 온도 180℃부터 분당 2℃씩 220℃까지 높혔다. 사용한 가스는 헬륨, 시료 주입량은 0.5㎕, 스플리트 레이시오는 50:1, 검출은 플레임 이오나이제이션 검출기로 하였다.Fatty acid composition was analyzed according to the Bligh and Byer method, the n-hexane layer was methyl esterified, dehydrated with anhydrous Na2SO4, filtered and analyzed by GC. For analysis, GC used Hewlett Packard 6890A (Palo Alto, CA, USA), and the column was HP FFAP.The injection port was 260 ° C, the detection port was 270 ° C, and the oven was 220 ° C for 2 ° C per minute. Raised up. The gas used was helium, the sample injection amount was 0.5 µL, the split race was 50: 1, and the flame ionization detector was detected.
결과를 하기의 표 5에 나타낸다(단위는 피크 면적%).The results are shown in Table 5 below (unit is peak area%).
실시예 12 및 비교예 1 및 2: 피토에스트로겐 분석Example 12 and Comparative Examples 1 and 2: Phytoestrogen Assay
실시예 4에서 얻은 흑석류 농축물과 비교예 1 및 2로서 대두 및 칡뿌리 농축물에 대하여 피토에스트로겐 분석을 수행하였다.The phytoestrogens analysis was carried out on the soybean and the root root concentrates as the black pomegranate concentrates obtained in Example 4 and Comparative Examples 1 and 2.
사용된 피토에스트로겐 표준품은 플라본, 헥사에스트롤, DES, 에쿠올, 크리신, 엔터로락톤, α-지랄라놀, 지랄라논, 17-β-에스트라디올, 바이오카닌-A, 카테킨, β-지랄에놀, α-지랄에놀, 다이드제인, 제니스테인, 카엠프페롤, 에피제님, 쿼르세틴의 20종이고, 에스트로겐류는 에스트론, 17-β-에스트라디올, 2-하이드록시에스트론, 2-하이드록시에스트라디올, 6-α-디하이드로에스트론, 6-α-하이드로시에스트라디올, 4-메톡시에스트라디올, 에스트리올, 16-에피에스트리올, 16,17-에피스트리올, 16-α-2-하이드록시에스트론, 17-에피에스트리올, 6-케토에스트리올, 2-메톡시에스트리올, 6-하이드록시에스트리올 및 16-케토에스트라디올의 16종이었으며, 내부 표준 물질은 d4-17β-에스트라디올로써 모두 Sigma사 미국 특급 시약을 사용하였다.The phytoestrogens standards used were flavones, hexaestrols, DES, equols, chrysins, enterolactones, α-giralanol, giralanone, 17-β-estradiol, biocanin-A, catechins, β-giral 20 kinds of enol, α-giralenol, dydzein, genistein, kaempferol, epigenim, quercetin, and estrogens are estrone, 17-β-estradiol, 2-hydroxyestron, 2- Hydroxyestradiol, 6-α-dihydroestrone, 6-α-hydroescistradiol, 4-methoxyestradiol, estriol, 16-epitriol, 16,17-epitriol, 16- 16 species of α-2-hydroxyestrone, 17-epitriol, 6-ketoestriol, 2-methoxyestriol, 6-hydroxyestriol and 16-ketoestradiol, internal standard The material was all d4-17β-estradiol using Sigma, USA.
표준 용액은 0.01g을 정확히 칭량한 다음, 메탄올로 1000ppm이 되게 만든 후 10배 희석한 것을 냉장 보관하여 사용하였다.The standard solution was used by weighing 0.01 g accurately, making 1000 ppm with methanol, and diluting 10 times with refrigeration.
유도체화 시약은 MSTFA(N-메틸-N-트리메틸실릴트리츨루오로아세트아미드)와 트리메틸클로로실란(TMCS)을 구입하여 STRA와 TMCS를 100:1(v/v)의 비율로 섞은 혼합 용액을 사용하였다.The derivatization reagent was purchased from MSTFA (N-methyl-N-trimethylsilyltrizluoacetamide) and trimethylchlorosilane (TMCS), and a mixed solution of STRA and TMCS in a ratio of 100: 1 (v / v) was prepared. Used.
Serdolit AD-2 수지(100-200 미크론)은 Serve사(독일)로부터 구입하였다.Serdolit AD-2 resin (100-200 microns) was purchased from Serve (Germany).
시료의 전처리와 분석 방법은 Chung 등의 방법을 참고하였다. 즉, 메탄올로 추출한 25mg의 시료에 내부 표준 d4-17β-에스트라디올 10㎍/㎖을 넣고 55℃에서 3시간 가수분해시킨 후 MSTFA/TMSC의 100:1 혼합물 50㎕을 가하고 60℃에서 30분간 반응시켜 TMS 에스터 유도체를 만든 후 이를 GC/MS에 2㎕ 주입하였다. 유도체화시켜 GC/MS에 주입하였다. 사용한 분석 기기는 Hwelette-Packard 5890 PIUS 가스 크로마토그라피에 디렉트 인터페이스로 연결된 5970 매스 셀렉티브 디텍터(MSD)를 사용하였다. 분리관은 울트라-2(길이 25mm, 내경 0.20mm, 필름 두께 0.33㎛를 사용하였으며, 분리관의 온도는 180℃에서 260℃까지 20℃/min으로 올리고 300℃까지 상승시켜 10분간 유지시켰다. 주입기의 온도는 300℃, 검출기의 온도는 300℃ 이동상 기체 헬륨의 유속은 0.85㎖/min 그리고 주입 방법은 스플리트 모드(비율 1:12)로 설정하였다. 이온화에 사용한 전자 에너지는 70eV였고 전처리된 시료들을 분석하기 위해 질량 스펙트럼상의 특성 이온만을 선택하여 검출하는 셀렉티드 이오 모니터링(SIM)방법을 이용하였다.For the pretreatment and analysis of samples, see Chung et al. In other words, 10 mg / ml of internal standard d4-17β-estradiol was added to 25 mg of the sample extracted with methanol, and hydrolyzed at 55 ° C. for 3 hours, and then 50 μl of a 100: 1 mixture of MSTFA / TMSC was added and reacted at 60 ° C. for 30 minutes. TMS ester derivative was prepared, and then 2 µl of the TMS ester derivative was injected into the GC / MS. Derivatized and injected into GC / MS. The analytical instrument used used a 5970 Mass Selective Detector (MSD) connected by direct interface to the Hwelette-Packard 5890 PIUS gas chromatography. The separator was Ultra-2 (length 25mm, inner diameter 0.20mm, film thickness 0.33㎛), the temperature of the separator was raised from 20 ℃ / min to 20 ℃ / min from 180 ℃ to 260 ℃ was maintained for 10 minutes. The temperature of the detector was set at 300 ° C., the detector at 300 ° C., and the flow rate of the mobile gas helium was 0.85 ml / min, and the injection method was set to the split mode (ratio 1:12) .The electron energy used for ionization was 70 eV, and the pretreated sample was used. Selected ion monitoring (SIM) method was used to select and detect only characteristic ions on the mass spectrum.
결과를 하기의 표 6에 나타낸다(단위는 ppm).The results are shown in Table 6 below (unit is ppm).
실시예 12 :Example 12:
안면홍조 현상을 겪고 있는 55~65세의 여성 30인을 15인씩 무작위로 2그룹으로 나누고 하나의 그룹에는 실시예 5에서 제조한 정제(흑석류 추출물 750mg/개)를 1일 9개씩 1개월간 복용하게 하고 다른 그룹에는 플레시보로써 흑석류 추출물 대신에 포도당으로 대체한 동일 형상의 정제를 1일 9개씩 3개월 복용케하고 안면홍조 현상의 완화 정도에 대하여 설문 조사하였으며, 그 결과를 하기의 표 7에 나타낸다.Thirty 55-65 year old women suffering from hot flashes were randomly divided into two groups of 15 people, and one group was to take the tablets prepared in Example 5 (750 mg / kg of black pomegranate extract) for nine months a day. Another group was asked to take nine tablets of the same shape three days a day instead of the black stone pomegranate extract instead of black pomegranate extract as a flashbo for the relief of hot flashes, and the results are shown in Table 7 below. .
상기 표에서 숫자는 완화되었다고 응답한 사람의 수이며 ( )의 숫자는 홍조 현상이 없어졌다고 응답한 사람의 숫자이다.In the above table, the number is the number of people who responded that it was alleviated and the number in parentheses was the number of people who answered that the flushing phenomenon disappeared.
상기한 결과로부터 본 발명에 따른 정제는 폐경으로 인한 안면홍조 현상의치료 및 예방에 탁월한 효과를 나타냄을 확인할 수 있었다.From the above results, it could be confirmed that the tablet according to the present invention had an excellent effect on the treatment and prevention of hot flashes due to menopause.
실시예 13 :Example 13:
본 발명에 따른 흑석류 추출물 함유 건강보조식품의 뼈 형성 촉진 여부를 평가하기 위하여 뼈 형성에 관계된 골아세포(osteoblast) 세포주(cell line)인 ROS 17/2.8을 사용하였다.ROS 17 / 2.8, which is an osteoblast cell line related to bone formation, was used to evaluate whether or not to promote bone formation of the black pomegranate extract-containing dietary supplement according to the present invention.
ROS 17/2.8 세포를 페놀레드가 첨가되지 않은 10% 송치혈청(fetal bovine serum)과 1% 항생제-항균제 혼합물(100 IU페니실린, 100 mg 스트렙토마이신, 250 ng 암포테리신)을 첨가한 둘베코 변형 이글배지(Dulbecco's Modified EagleMedium)에 접종하고 37℃, 5% CO2인큐베이터에서 배양하였다. 세포증식은 엠티티(MTT; 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolin bromide)의 대사환원 원리를 통한 엠티티 에세이(MTT assay) 방법과 방사성 표지된 티미딘(3H-Thymidine) 방사능 활성을 통한 티미딘 편입 에세이(incorporation assay)로 측정하였다.Dulbecco's modification of ROS 17 / 2.8 cells with 10% fetal bovine serum without phenol red and 1% antibiotic-antibacterial mixture (100 IU penicillin, 100 mg streptomycin, 250 ng amphotericin) Inoculated in Dulbecco's Modified EagleMedium and incubated in 37 ° C., 5% CO 2 incubator. Cell proliferation was performed by MTT assay and radiolabeled thyme through metabolic reduction principle of MTT (3- (4,5-dimethyl-thiazol-2-yl) -2,5-diphenyltetrazolin bromide). It was measured by a thymidine incorporation assay through din ( 3 H-Thymidine) radioactivity.
상기한 실시예 3에서의 추출물을 평가하였으며, 대두에서 분리한 제니스테인을 비교대조군으로, 시료 무첨가군을 대조군(control)으로 설정하여 증식정도를 비교하였다.The extract in Example 3 was evaluated, and the growth rate was compared by setting the genistein isolated from the soybean as a comparative control and the sample-free group as a control.
먼저, ROS 17/2.8 세포를 96-웰(well)에 8% 에스트로겐 결핍-FBS 배지로 세포수 2x103으로 접종하고 송치혈청의 효과를 배제하기 위해 24시간 동안 0.8% 에스트로겐 결핍-송치 혈청으로 배지 조성을 바꾸어 주었으며, 2.5% 에스트로겐 결핍-송치혈청 조건 하에서 흑석류 추출물로부터의 피토에스트로겐 혼합물(실시예 12) 및 제니스테인(10-9및 10-12몰농도)로 48시간 동안 자극하였다. 각 웰(well)에 75㎕ 엠티티(1.6 ㎎/mL) 용액을 첨가하여 37℃에서 3시간동안 반응시킨 후, 디메틸슬폭사이드(dimethylsulfoxide) 75㎕를 첨가하여 세포에 형성된 포르마잔 결정체(formazan crystal)을 용해시켰다. 흡광도는 마이크로플레이트 판독기를 이용하여 540nm에서 측정하였다. 이어서, 동일 세포를 24-웰에 세포수가 1x104으로 접종하고, 전술한 바와 동일하게 자극을 주었다. 자극 종결 4시간 전에 방사능 표지된 티미딘 용액을 한 웰당 1μc씩 첨가하여 37℃에서 배양하였다. 배양한 세포는 3% 트리클로로아세테이트 용액으로 침전물을 형성시킨 후, 2% 디소디움카보네이트 용액을 200㎕씩 첨가하여 용해시켰다. 베타 카운터에서 방사능 활성도를 측정하였다. 뼈 형성 촉진능은 대조군에 대한 상대치로 나타냈다.First, ROS 17 / 2.8 cells were seeded in 96-wells with cell count 2 × 10 3 with 8% estrogen deficient-FBS medium and cultured with 0.8% estrogen deficient-transmitted serum for 24 hours to rule out the effects of the deceased serum. The composition was changed and stimulated for 48 hours with phytoestrogens mixture (Example 12) and genistein (10 -9 and 10 -12 molar concentrations) from the Black Pomegranate extract under 2.5% estrogen deficiency-transmitted serum conditions. A 75 μl empty (1.6 mg / mL) solution was added to each well, followed by reaction at 37 ° C. for 3 hours, followed by addition of 75 μl of dimethylsulfoxide to formazan crystals formed on cells. ) Was dissolved. Absorbance was measured at 540 nm using a microplate reader. Subsequently, the same cells were seeded in a 24-well cell number 1 × 10 4 and stimulated as described above. Four hours before the end of stimulation, radiolabeled thymidine solution was added at 1 μc per well and incubated at 37 ° C. The cultured cells were precipitated with 3% trichloroacetate solution and lysed by adding 200 μl of 2% disodium carbonate solution. Radioactivity was measured on the beta counter. The ability to promote bone formation was expressed relative to the control.
결과를 하기의 표 8에 나타낸다.The results are shown in Table 8 below.
상기의 표 8로부터 확인되는 바와 같이, 실시예 3에서의 피토에스트로겐 혼합물은 낮은 농도인 10-12M에서 이미 117%의 세포 증식 효과를 나타내었으며, 생리적농도인 10-9M에서는 약 126%까지 증가하여 용량 의존적으로 골아세포의 증식을 촉진하였다. 대두의 제니스테인도 골아세포 증식을 최고 113% 증가시켰지만 실시예 3의 피토에스트로겐 혼합물 보다는 훨씬 낮은 효과를 나타내는 것으로 확인되었다.As can be seen from Table 8 above, the phytoestrogens mixture in Example 3 already exhibited a cell proliferation effect of 117% at low concentrations of 10 -12 M and up to about 126% at physiological concentrations of 10 -9 M. Increased dose-dependently promoted proliferation of osteoblasts. Genistein in soybean also increased osteoblast proliferation up to 113%, but was found to have a much lower effect than the phytoestrogens mixture of Example 3.
실시예 14 :Example 14
본 발명에 따른 흑석류 추출물 함유 건강보조식품의 뼈 형성 촉진 여부를 평가하기 위하여 마우스 태아의 미분화 골아세포주인 KS483 세포를 36-웰 플레이트에 세포수 2.4×104으로 접종한 후, 세포가 완전히 증식하여 밀집 상태에 달하였을 때 8% 송치 혈청 조건 하에 실시예 13과 동일한 조건으로 세포를 자극하였다. 제니스테인은 비교군으로, 시료 무첨가군은 대조군으로 설정하였다.In order to evaluate the bone formation of the dietary supplement containing black pomegranate extract according to the present invention, after inoculating KS483 cells, which are undifferentiated osteoblasts of mouse fetus, with a cell number of 2.4 × 10 4 in a 36-well plate, the cells proliferated completely. When the cells reached a dense state, the cells were stimulated under the same conditions as in Example 13 under 8% inverted serum conditions. Genistein was set as a control group and the sample-free group was set as a control group.
세포분화유도물질인 아스콜빈산(43㎍/mL), 베타-글리세로포스페이트 3mM 및 덱사메타존 5nM을 2일마다 첨가하여 3주 동안 배양하면서, 일정 시점마다 세포염색하여 분화 촉진정도를 비교하였다.Cell differentiation-inducing substances ascorbic acid (43㎍ / mL), beta-glycerophosphate 3mM and dexamethasone 5nM were added every 2 days, and cultured for 3 weeks, and cell staining at each time point was compared to promote differentiation. .
분화 유도 3주 째에는 질산은으로 본코사 염색을 하여 형성된 노듈 수를 비교하였다. 분화촉진작용은 대조군에 대한 상대치로 나타냈다.At 3 weeks of induction of differentiation, the number of nodules formed by Boncosa staining with silver nitrate was compared. Differentiation promoting action is shown relative to the control.
상기한 표 9의 결과로부터, 실시예 3에서의 피토에스트로겐 혼합물은 낮은 농도인 10-12M에서 이미 2배의 세포분화촉진 효과를 나타내었으며, 생리적 농도인 10-9M에서는 3.4배까지 증가시키는 용량-의존적인 분화촉진효과를 나타냄을 확인할 수 있었다. 한편, 대두의 제니스테인은 생리적 농도에서 0.9배 정도의 분화를 나타냈다.From the results of Table 9 above, the phytoestrogens mixture in Example 3 already showed a two-fold cell differentiation promoting effect at a low concentration of 10 -12 M, and increased to 3.4 times at a physiological concentration of 10 -9 M It can be seen that it shows a dose-dependent differentiation promoting effect. On the other hand, genistein of soybean showed about 0.9-fold differentiation at physiological concentrations.
따라서, 본 발명의 흑석류 추출물 함유 건강보조식품은 매우 우수한 골아세포 분화효과를 갖는 것으로 판단되었다.Therefore, the black pomegranate extract-containing dietary supplement was determined to have a very good osteoblast differentiation effect.
실시예 15 :Example 15:
본 발명에 따른 흑석류 추출물 함유 건강보조식품의 골다공증 억제 효과를 평가하기 위하여, 스프라구돌리(Sprague-Dawley) 12주령의 암마우스(평균 체중 240g)를 펜토바비탈(pentobarbital) 마취 하에 양쪽 난소를 적출하고, 대조군 마우스는 가수술(sham)을 하였다. 난소를 제거하고 난 다음, 1주일 후에 마우스를 다음과 같은 3개의 그룹으로 나누었다.In order to evaluate the osteoporosis inhibitory effect of the black pomegranate extract-containing dietary supplement, both ovaries were extracted under pentobarbital anesthesia for 12-week-old Sprague-Dawley female mice (average weight 240 g). The control mice were sham. After removing the ovaries, one week later the mice were divided into three groups:
실시예 6의 식이(5㎖/kg/1일)를 먹인 그룹, 에스트로겐을 주당 2회 피하 주사(50㎍/100㎕ 대두유)한 그룹, 대조 식이를 먹인 대조군으로 나누었다. 난소 제거한 4주 후에 쥐를 희생하여 뒷다리 경골(tibia)을 분리하였다.The group fed the diet of Example 6 (5 ml / kg / day), the subcutaneous injection of estrogen twice a week (50 μg / 100 μl soybean oil), and the control group fed the control diet. Four weeks after the ovary removal, the rats were sacrificed to separate the hind tibia.
경골은 분리 즉시, 포르말린 고정액에 넣어 보관하였다가 탈회하여 근위 골간단(proximal metaphysis) 부위를 5㎛로 횡절하였다. 골다공증의 정도는 소주골밀도(trabecular bone density), 피질골 두께(cortical bone thickness), 골수강에서 지방적이 차지하는 비율(adipocyte density)로 판정하였다. 각각의 결과를 가수술군에 대한 상대치로 나타냈으며, 그룹간의 차이는 일변량분산분석을 통해 검정하였다.The tibia was immediately stored in formalin fixative and demineralized, and the proximal metaphysis site was traversed to 5 μm. The degree of osteoporosis was determined by trabecular bone density, cortical bone thickness, and adipocyte density in the bone marrow cavity. Each result was expressed as a relative value to the singer group, and the difference between groups was tested by univariate variance analysis.
상기한 표 10으로부터 확인되는 바와 같이, 난소제거 4주 후 무처리군의 경골의 소주골밀도는 가수술한 대조군의 13%까지 감소하여 심한 골다공증을 나타냈으며, 난소 제거 후 에스트로겐을 투여한 쥐의 골밀도는 대조군의 약 83%로서 골다공의 진행이 효과적으로 억제되었음을 확인할 수 있었다. 한편, 난소 제거 후 실시예 3의 식이를 먹인 마우스의 골밀도는 대조군의 62%였다. 이는 에스트로겐 보다는 낮지만 난소제거로 생기는 골다공증의 골밀도 보다 5배 이상 높은 값으로서, 본 발명에 따른 건강보조식품 섭취시 골다공증의 진행이 유의하게 억제될 수 있다는 가능성을 강하게 시사하는 것으로 해석되었다.As can be seen from Table 10 above, after 4 weeks of ovarian removal, the bone mineral density of the tibia in the untreated group decreased to 13% of the control group, indicating severe osteoporosis, and bone density of the estrogen-treated rats after ovarian removal. Was about 83% of the control group was confirmed that the progress of osteoporosis was effectively suppressed. On the other hand, the bone density of the mice fed the diet of Example 3 after ovarian removal was 62% of the control group. This is lower than estrogen, but more than five times higher than the bone density of osteoporosis caused by ovarian removal, it was interpreted strongly suggesting that the progression of osteoporosis can be significantly inhibited when the dietary supplement intake according to the present invention.
난소 제거 후 소주골이 흡수되어 골다공증이 진행됨에 따라 무처리군의 경우에는 골수 내 지방세포 밀도는 2.8배 증가하는 반면, 난소제거 후 인위적으로 에스트로겐을 피하 투여한 경우에는 골수 내 지방축적은 약 36% 정도 증가하였다. 반면에, 난소 제거 후 실시예 3의 식이를 먹인 마우스의 골수 내 지방축적 증가는 대조군의 16.8%에 그쳤다. 따라서, 이러한 결과는 본 발명에 따른 건강보조식품 섭취시 합성 에스트로겐 투여시의 부작용인 지방 증가 현상이 훨씬 적다는 것을 나타낸다.As osteoporosis progressed after the ovarian removal, the bone marrow fat cell density increased by 2.8 times in the untreated group, whereas in the case of artificially subcutaneous administration of estrogen after ovarian removal, the fat accumulation in the bone marrow was about 36 % Increased. In contrast, the increase in bone marrow fat accumulation in the mice fed the diet of Example 3 after ovarian removal was only 16.8% of the control group. Therefore, these results indicate that the increase in fat, which is a side effect of the administration of synthetic estrogen, when the dietary supplement according to the present invention is much less.
실시예 16Example 16
아테롬성 동맥경화증에 대한 영향 조사를 위하여, 하룻 동안 단식시켜 고지혈증을 유발시킨 웅성 마우스를 선택하여 실험하였다. 3일간 비타민 D2와 콜레스테롤을 각각 80,000 ed/100 g과 20 mg/100g씩 투여하여 비타민-콜레스테롤 고지혈증을 일으킨 것과 트리톤 WP-1339 225 mg/kg을 복강 투여하여 내인성 고지혈증을 유발한 것을 사용하였다. 그 다음, 트리톤을 투여한 20시간 후 및 비타민과 콜레스테롤 혼합물을 투여한 20시간 후 지질의 양을 측정하였다. 실시예 4의 추출물은 고지혈증 유발 전 3일간 및 희생시키기 3시간 전에 3mg/kg의 양으로 4회 투여하였다.In order to investigate the effects on atherosclerosis, male mice that were fasted for one day to cause hyperlipidemia were selected and tested. Vitamin D2 and cholesterol were administered 80,000 ed / 100 g and 20 mg / 100g for 3 days, respectively, and vitamin-cholesterol hyperlipidemia was induced and intraperitoneal administration of Triton WP-1339 225 mg / kg was used. The amount of lipid was then measured 20 hours after Triton and 20 hours after the administration of the vitamin and cholesterol mixture. The extract of Example 4 was administered four times in an amount of 3 mg / kg 3 days before hyperlipidemia induction and 3 hours before sacrifice.
내인성 고지혈증의 경우, 초기 콜레스테롤 농도는 0.83±0.07mmol/ℓ, 트리글리세라이드 양은 0.28±0.003mmol/ℓ였으나, 고지혈증의 유발에 의해 혈장의 콜레스테롤과 트리글리세라이드 농도는 각각 3.26±0.05mmol/ℓ과 0.51±0.04mmol/ℓ로 증가하였으나, 실시예 4의 추출물을 투여한 경우 0.65±0.02mmol/ℓ과 0.26±0.021mmol/ℓ로 각각 크게 감소하였다. 또한, 트리톤을 투여한 경우 혈중 트리글리세라이드 양은 8.2 ±0.41mmol/ℓ로 29배 증가하였으며, 콜레스테롤양은 5.45±0.13mmol/ℓ로서 6.7배 증가하였다. 한편, 실시예 4의 추출물을 투여한 경우, 콜레스테롤 양은 2.76±0.24 mmol/ℓ로 감소하였으나, 혈중 트리글리세라이드 양에는 변화가 없었다.In the case of endogenous hyperlipidemia, the initial cholesterol level was 0.83 ± 0.07mmol / l and the amount of triglyceride was 0.28 ± 0.003mmol / l. It increased to 0.04 mmol / L, but the extract of Example 4 significantly decreased to 0.65 ± 0.02 mmol / L and 0.26 ± 0.021 mmol / L, respectively. In addition, the amount of triglyceride in blood increased by 29 times to 8.2 ± 0.41 mmol / l and the amount of cholesterol increased by 6.7 times to 5.45 ± 0.13 mmol / l. On the other hand, when the extract of Example 4 was administered, the amount of cholesterol decreased to 2.76 ± 0.24 mmol / L, but there was no change in the amount of triglycerides in the blood.
한편, 비타민-콜레스테롤 고지혈증의 경우, 콜레스테롤과 트리글리세라이드의 혈중 농도는 초기농도에 비해 3.2배 증가하였으나, 실시예 4의 추출물을 투여한 경우에는 콜레스테롤의 양은 정상화되었으며, 트리글리세라이드 양은 증가하였다.On the other hand, in the case of vitamin-cholesterol hyperlipidemia, the blood concentrations of cholesterol and triglyceride increased 3.2 times compared to the initial concentration, but when the extract of Example 4 was administered, the amount of cholesterol was normalized and the amount of triglyceride was increased.
위의 결과로부터 본 발명에 따른 건강보조식품은 콜레스테롤 및 트리글리세라이드의 농도를 효과적으로 저감시킨다는 사실이 확인되었다.From the above results it was confirmed that the dietary supplement according to the present invention effectively reduces the concentration of cholesterol and triglycerides.
실시예 17Example 17
추출물이 중추신경계에 미치는 영향을 조사하기 위하여 실시예 4의 추출물 3∼10mg/kg을 우레탄으로 인한 혼수상태의 고양이와 모르핀-우레탄 혼수상태의 개에 정맥투여하여 급성독성 실험을 수행한 결과, 약 3분간 약한 동맥혈압의 상승(3∼7%)이 있고 아드레날린의 동맥자극 효과가 약간 상승하는 경향이 있었으나, 히스타민과 아세틸콜린을 투여하면 이러한 동맥압에는 변화가 인지되지 않았다.In order to investigate the effect of the extract on the central nervous system, the acute toxicity test was performed by intravenously administering 3 to 10 mg / kg of the extract of Example 4 to the urine coma and the morphine-urethane coma. There was a slight increase in arterial blood pressure (3-7%) for 3 minutes and a slight increase in the arterial stimulation effect of adrenaline, but no change was observed in the arterial pressure with the administration of histamine and acetylcholine.
이러한 결과로부터, 본 발명에 따른 이란산 흑석류 추출물 및 이를 포함하는 건강보조식품은 급성독성을 전혀 일으키지 않음과 아울러, 중주신경계의 기능 등에도 하등의 영향을 미치지 않는다는 사실을 확인하였다.From these results, it was confirmed that the Iranian black pomegranate extract and the health supplement containing the same according to the present invention did not cause any acute toxicity, and also had no effect on the function of the midweek nervous system.
상술한 바와 같이, 본 발명에 따른 석류 추출물과 이를 유효성분으로서 포함하는 건강보조식품은 우수한 에스트로겐성을 나타내면서도 부작용이 거의 없는 안전한 피토에스트로겐을 다량 함유하고 있으므로, 갱년기 또는 폐경기 여성에 있어서의 에스트로겐 결핍으로 인하여 유발될 수 있는 제반 증상을 효과적으로 예방 및 치료할 수가 있을 것으로 기대된다. 특히, 본 발명에 따른 추출물 및 이를 포함하는 건강보조식품은 안면홍조, 골다공증, 아테롬성 심장질환에 탁월한 효과를 나타내면서도, 부작용으로서의 체지방 증가 현상이 매우 낮으므로, 건강보조식품으로서 뿐만 아니라, 피토에스트로겐 분리물을 생물의약으로서도 사용할 수 있을 것으로 기대되는 신규 유용한 발명이다.As described above, the pomegranate extract and the dietary supplement comprising the same as an active ingredient contain a large amount of safe phytoestrogens with excellent estrogen properties and little side effects, and thus, estrogen deficiency in menopausal or postmenopausal women. It is expected to be able to effectively prevent and treat all the symptoms that can be caused by. In particular, the extract and the health supplement comprising the same according to the present invention have excellent effects on hot flashes, osteoporosis, atherosclerosis, and very low body fat increase as a side effect, not only as a dietary supplement, but also phytoestrogene separation It is a novel useful invention which is expected to be able to use water as a biomedical agent.
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KR102514059B1 (en) | 2022-07-12 | 2023-03-27 | (주)스마트푸릇 | Fermented pomegranate composition for improving bone health or female menopausal symptoms, containing high content of ellagic acid and gallic acid with increased absorption into the body and its use having skin whitening, wrinkle improvement or antioxidant function, and method for manufacturing the same by using EFC method |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH05320037A (en) * | 1992-05-20 | 1993-12-03 | Tsuneo Nanba | Antioxidation agent |
IT1299191B1 (en) * | 1998-06-23 | 2000-02-29 | Sigma Tau Healthscience Spa | COMPOSITION TO PREVENT AND TREAT OSTEOPOROSIS AND ALTERATIONS RELATED TO MENOPAUSE |
KR100348148B1 (en) * | 2001-12-10 | 2002-08-09 | 한국 한의학 연구원 | Extract of Puerariae Radix for the prevention and treatment of osteoporosis |
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Cited By (4)
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KR100580070B1 (en) * | 2004-07-07 | 2006-05-16 | 주식회사 엘지생활건강 | Food for whitening of skin |
WO2010076913A1 (en) * | 2009-01-05 | 2010-07-08 | Health-Love Co., Ltd | Pomegranate extracts from pomegranate flesh, and composition for improving postmenopausal syndrome comprising effective amount of the same |
KR101143255B1 (en) * | 2010-04-08 | 2012-05-03 | (주) 건강사랑 | Pomegranate extract containing a high content of ellagic acid, and a method for improving effect of pomegranate extract related to anxiety disorders, depression or attention disorders |
EP2628485A4 (en) * | 2010-10-14 | 2014-03-26 | Univ Tianjin Traditional Chinese Medicine | New use of chemical ingredients in cynomorium as phytoestrogen |
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