KR100497949B1 - Extract of herb for promoting release of growth hormone - Google Patents
Extract of herb for promoting release of growth hormone Download PDFInfo
- Publication number
- KR100497949B1 KR100497949B1 KR10-2002-0035775A KR20020035775A KR100497949B1 KR 100497949 B1 KR100497949 B1 KR 100497949B1 KR 20020035775 A KR20020035775 A KR 20020035775A KR 100497949 B1 KR100497949 B1 KR 100497949B1
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- South Korea
- Prior art keywords
- growth hormone
- extract
- alcohol
- present
- water
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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
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- 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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- A—HUMAN NECESSITIES
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
-
- A—HUMAN NECESSITIES
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Botany (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
본 발명은 둥굴레(Polygonati Odorati Rhizoma) 추출물의 제조방법, 상기 방법에 의해 얻어지는 둥굴레 추출물 및 이를 포함하는 약학적 조성물 및 건강식품에 관한 것으로서, 보다 구체적으로는 둥굴레를 알콜 또는 알콜과 물의 혼합 용매를 첨가하거나 산 또는 염기 용액으로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합 용매를 첨가하여 추출되는 둥굴레 추출물의 제조방법, 상기 방법에 의해 얻어지는 둥굴레 추출물 및 이를 유효성분으로 포함하는 약학적 조성물 및 건강식품에 관한 것이다. 본 발명의 둥굴레 추출물은 강력한 성장호르몬 분비촉진 활성을 나타내며 천연약재로서 안전성이 확보되어 있으므로 성장호르몬 분비촉진제용 의약품 및 식품으로 유용하게 사용될 수 있다.The present invention relates to a method for preparing a Polygonati Odorati Rhizoma extract, a pharmaceutical composition and a health food comprising the same, and more specifically, to a dongle is added alcohol or a mixed solvent of alcohol and water. Or a method for producing a extract of the donggule extracted by adding an alcohol or a mixed solvent of alcohol and water, neutralizing the hydrolyzate with an acid or base solution, and extracting the donggulle extract obtained by the method and a pharmaceutical composition and health food comprising the same as an active ingredient. It is about. The extract of the present invention exhibits potent growth hormone secretagogue activity and can be used as a growth hormone secretagogue medicinal product and food because it is safe as a natural medicine.
Description
본 발명은 둥굴레(Polygonati Odorati Rhizoma) 추출물의 제조방법, 상기 방법에 의해 얻어지는 둥굴레 추출물 및 이를 포함하는 약학적 조성물 및 건강식품에 관한 것으로서, 보다 구체적으로는 둥굴레를 알콜 또는 알콜과 물의 혼합 용매를 첨가하거나 산 또는 염기 용액으로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합 용매를 첨가하여 추출되는 둥굴레 추출물의 제조방법, 상기 방법에 의해 얻어지는 둥굴레 추출물 및 이를 유효성분으로 포함하는 약학적 조성물 및 건강식품에 관한 것이다.The present invention relates to a method for preparing a Polygonati Odorati Rhizoma extract, a pharmaceutical composition and a health food comprising the same, and more specifically, to a dongle is added alcohol or a mixed solvent of alcohol and water. Or a method for producing a extract of the donggule extracted by adding an alcohol or a mixed solvent of alcohol and water, neutralizing the hydrolyzate with an acid or base solution, and extracting the donggulle extract obtained by the method and a pharmaceutical composition and health food comprising the same as an active ingredient. It is about.
성장호르몬(growth hormone, GH)은 동물의 뇌하수체에서 분비되는 단백질로서 191개의 아미노산으로 구성된 펩타이드 호르몬이다. 이러한 성장호르몬은 오래 전부터 동물체로부터 분리되어 주로 왜소증(dwarfism, 난장이병) 환자들의 치료에 사용되어 왔는데, 단백질의 손실을 억제하고 나이가 많은 장년 또는 노인에서 생리학적인 노화 현상을 지연시키는 작용이 있으므로 다양한 질병의 치료에 사용될 수 있다(Horber, F. F. and Haymond, M.W., J. Clin. Invest., 1990, 86, 265-272).Growth hormone (GH) is a protein secreted by the pituitary gland of animals and is a peptide hormone consisting of 191 amino acids. These growth hormones have been isolated from animals for a long time and have been used mainly for the treatment of dwarfism patients. They have various effects because they inhibit protein loss and delay physiological aging in older adults or the elderly. It can be used to treat diseases (Horber, FF and Haymond, MW, J. Clin. Invest ., 1990, 86, 265-272).
성장호르몬을 지속적으로 투여하면 체중, 근육 및 지방의 무게 등이 증가하여 노화로 인한 질병을 예방할 수 있고, 일시적으로 투여하는 경우에도 혈장내의 인슐린 및 IGF-1(Insulin-like growth factor-1)의 농도를 증가시키며 소변 내의 단백질 농도를 감소시키는 것으로 알려져 있으며(Kohrt, W. M. et al., Med. Sci. Sports Exerc., 1992, 24, 832-837; Zachweija, J. J. et al., Am. J. Physiol., 1994, 266 (Endocrinol. Metab. 29), E840-844), 이외에도 간의 무게와 크기를 증가시키고 근육, 뼈 및 연결 조직 등의 말단 조직에서 단백질의 합성을 향상시키는 것으로 보고되었다(Kaiser, F. E. et al., J. Am. Geriatr. Soc., 1991, 39, 235-240; Marcus, R. et al., J. Clin. Endocrino. Metab., 1990, 70, 519-527).Continuous administration of growth hormone increases body weight, muscle, and fat weight to prevent aging-related diseases. Even when administered temporarily, plasma insulin and IGF-1 (Insulin-like growth factor-1) It is known to increase the concentration and decrease the protein concentration in urine (Kohrt, WM et al., Med. Sci. Sports Exerc ., 1992, 24, 832-837; Zachweija, JJ et al., Am. J. Physiol , 1994, 266 (Endocrinol. Metab. 29), E840-844), as well as increasing the weight and size of the liver and improving the synthesis of proteins in terminal tissues such as muscle, bone and connective tissue (Kaiser, FE). et al., J. Am. Geriatr. Soc ., 1991, 39, 235-240; Marcus, R. et al., J. Clin. Endocrino. Metab ., 1990, 70, 519-527).
지금까지의 연구로는 선천적인 뇌하수체 기능부전(hypopituitarism)인 어린이와 성인에게 성장호르몬 분비촉진 호르몬(growth hormone releasing hormone, 이하 "GHRH"라 칭한다)과 아르기닌(arginine)을 동시에 투여했을 때 그 효과는 성인보다도 어린이에게서 성장호르몬의 감응정도가 높았으며 많은 종류의 뇌하수체호르몬 결핍 환자보다도 성장호르몬 결핍 환자에게서 감응정도가 더 높았고 완전한 뇌하수체계를 갖는 환자보다도 뇌하수체의 잔여 맥관 성분(residual vascular component)을 가진 환자에게서 더 높은 결과를 얻었다. GHRH와 아르기닌에 대한 성장호르몬의 반응성은 나이에 따라 감소하는 경향(J. Clin. Endocrinol. Metab., 2001, 86(4), 1574-79)이 있고, 성장호르몬 분비촉진제(secretagogue)에 대한 내생 리간드인 그레린(ghrelin)을 성장호르몬 결핍 쥐에 투여하였을 때 효과가 있었으며(Diabetes, 2001, 50(2), 227-32), 활성 성장호르몬 분비촉진제인 MK-677과 강력한 골 흡수 저해제인 아렌드로네이트(alendronate)를 함께 투여하면 아렌드로네이트를 단독 투여했을 때보다 상대적으로 더 높은 형성 속도를 유지하므로 폐경후 골다공증인 여성에게서 골 무기질 밀도(bone mineral density)를 증가시킨다. MK-677과 아렌드로네이트의 병행 투여의 IGF-1 레벨에 대한 영향은 MK-677 단독 투여나 아렌드로네이트와 병행 투여 모두 IGF-1 레벨이 증가하고 골 형성 감소를 완화시켰으며 대퇴 목(femoral neck)의 골 무기질 밀도는 증가한 반면 요추, 둔부의 골 무기질 밀도는 증가 현상이 나타나지 않았다. MK-677을 통한 성장호르몬의 대사효과는 골 형성에 있어서 아렌드로네이트의 직접적인 억제효과를 줄였다(J. Clin. Endocrinol. Metab., 2001, 86(3), 1116-25).Until now, the effects of simultaneous growth hormone releasing hormone (GHRH) and arginine on children and adults with congenital hypopituitarism have been shown to be effective. Growth hormone response was higher in children than in adults, and growth hormone deficiency was higher in patients with growth hormone deficiency than in many types of pituitary hormone deficiency, and patients with residual vascular components of the pituitary gland Obtained higher results. Responsiveness of growth hormone to GHRH and arginine tends to decrease with age ( J. Clin. Endocrinol. Metab ., 2001, 86 (4), 1574-79), and endogenous growth hormone secretagogues. Ghrelin, a ligand, was effective when administered to growth hormone deficient rats ( Diabetes , 2001, 50 (2), 227-32). The administration of alrondron (alendronate) increases bone mineral density in postmenopausal women with postmenopausal osteoporosis because it maintains a relatively higher rate of formation than when arendronate is administered alone. The effect of MK-677 and arendronate on IGF-1 levels was increased in both MK-677 alone or in combination with arendronate and increased IGF-1 levels and alleviated decreased bone formation. The bone mineral density of the neck increased while the bone mineral density of the lumbar spine and hip did not increase. The metabolic effect of growth hormone through MK-677 reduced the direct inhibitory effect of arendronate on bone formation ( J. Clin. Endocrinol. Metab ., 2001, 86 (3), 1116-25).
과거에 성장호르몬은 주로 사체의 뇌하수체로부터 추출되어 사용되었으나, 이 과정에서 성장호르몬을 투여 받은 환자들에게 크로이츠펠트-야콥병 (Creutzfeldt-Jakob disease)이란 질병을 유발시킴이 밝혀졌다. 이렇게 분리 과정에서 다른 질병의 원인 물질까지 환자에게 유입될 수 있는 위험성이 있어 사체로부터 분리한 성장호르몬은 그 사용이 매우 제한되었다. 유전공학의 발달과 더불어 미생물을 이용하여 생산한 재조합 성장호르몬은 대량 생산 및 공급이 가능하고 다른 질환의 감염 위험성이 적으므로 왜소증 치료제 시장의 대부분을 재조합 성장호르몬을 포함하는 단백질 제제가 차지하게 되었다. 유전자 재조합 방식의 성장호르몬을 체내에 투여하는 방법은 성장호르몬 자체가 거대 단백질이어서 경구투여가 불가능하여 주사기를 이용한 근육주사로 이루어진다. 이와 같이 재조합 성장호르몬은 대량 생산될 수 있음에도 불구하고 일정한 치료 기간동안 요구되는 비용이 상당하고, 경구투여가 불가능하여 주사를 이용해야 하는 불편함으로 인하여 최근에는 경구 투여용 제제를 개발하려는 시도들이 활발히 진행되고 있다.In the past, growth hormone was mainly extracted from the cadaveric pituitary gland, but in the process it was found to cause the disease Creutzfeldt-Jakob disease in patients receiving growth hormone. As such, there is a risk that other diseases may be introduced into the patient during the separation process, and growth hormone isolated from the carcass has been limited in its use. With the development of genetic engineering, recombinant growth hormone produced using microorganisms can be produced and supplied in large quantities, and the risk of infection of other diseases is low, so the protein preparation including recombinant growth hormone occupies most of the market for dwarfism. The method of administering the recombinant recombinant growth hormone into the body is made by intramuscular injection using a syringe because the growth hormone itself is a huge protein and cannot be orally administered. As such, although recombinant growth hormone can be mass produced, attempts to develop oral preparations have been actively conducted in recent years due to the high cost required for a certain treatment period and the inability to use injection because it is impossible to orally administer. It is becoming.
경구 투여용 성장호르몬 제제의 기본 요건은 체내에서 흡수율이 높아야 하는 동시에, 선택적으로 성장호르몬 분비를 자극할 수 있는 생물학적 활성도를 지니고 있어야 하는 것이다. 경구 투여로 체내에서 높은 흡수율을 갖기 위해서는 분자량이 작을수록 유리하며, 체내에서 생리 활성 작용을 원활하게 수행하려면 구조적으로도 특별한 물리화학적 성질을 가져야 한다.The basic requirement for growth hormone preparations for oral administration is to have high absorption rate in the body and to have biological activity that can selectively stimulate growth hormone secretion. In order to have a high absorption rate in the body by oral administration, the smaller the molecular weight is advantageous, and to perform the physiological activity in the body smoothly, it must have a special physical and chemical properties.
이와 같은 기본 요건을 갖춘 물질로서 연구되어 임상시험 단계까지 개발된 대표적인 것들로는 유기합성된 L-692, 429(Horm. Res., 1993, 40, 109-115) 및 L-163, 191(PNAS, 1995, 92, 7001-7005), 그리고 펩타이드성 화합물 GHRP-2(Endocrinology, 1994, 140, R9-R13), GHRP-1(J. Neuroendocrinology, 1994, 6, 185) 및 헥사렐린(Hexarelin: His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) 등이 있다. 상기 물질들은 공통적으로 1980년대 초에 알려진 펩타이드성 화합물인 GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2)의 기본 구조를 이용하여 새로이 연구 개발된 것이다.Representatives that have been studied as substances with these basic requirements and have been developed up to the clinical trial stage include organically synthesized L-692, 429 ( Horm. Res. , 1993, 40, 109-115) and L-163, 191 ( PNAS). , 1995, 92, 7001-7005), and the peptide compounds GHRP-2 ( Endocrinology , 1994, 140, R9-R13), GHRP-1 ( J. Neuroendocrinology , 1994, 6, 185) and hexarelin (Hexarelin: His -D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2). The materials are newly researched and developed using the basic structure of GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2), a peptide compound commonly known in the early 1980s.
최근에는 새로운 물질을 개발하는 접근 방식으로 화학물질 라이브러리(chemical library)를 이용하여 후보 물질들을 대량 검색하는 방법이 각광을 받고 있으며, 이외에도 길이가 짧은 펩타이드들로 구성된 펩타이드 라이브러리(peptide library) 및 자연계에 존재하는 여러 물질들로 구성된 천연물질 라이브러리(natural library)도 이러한 새로운 물질을 개발하기 위하여 활용되고 있다. 이와 같이 다양하고 광범위한 라이브러리를 이용하여 신약을 개발하는 것은 개발에 소요되는 기간 및 비용 면에서 기존의 접근 방식보다 상당히 효율적이므로 선진 제약기업에서는 이미 오래 전부터 자사의 라이브러리를 이용한 신약 개발에 적극적으로 참여하여 왔다. 구체적으로 상기 L-163, 191 및 헥사렐린도 이러한 접근 방식으로 개발된 물질이라 할 수 있다.Recently, the approach of developing a new material has been in the spotlight by using a chemical library to search for a large amount of candidates, and in addition to the peptide library composed of short peptides and the natural world, Natural libraries consisting of many existing materials are also used to develop these new materials. Developing new drugs using such a wide variety of libraries is considerably more efficient than traditional approaches in terms of the time and cost of development, so developed pharmaceutical companies have long been active in developing new drugs using their libraries. come. Specifically, L-163, 191, and hexarelin may be referred to as substances developed by this approach.
원래 체내에는 동물마다 다르지만 사람의 경우 44개의 아미노산으로 구성된 GHRH가 존재한다. 사람의 체내에서 성장호르몬의 분비를 조절하는 것은 성장호르몬의 분비를 촉진하는 GHRH와 성장호르몬의 분비를 억제하는 소마토스타틴 (Somatostatin)이라는 호르몬이며 이들은 상호작용을 통해 성장호르몬을 간헐적 (pulsatile)으로 특이하게 분비하도록 작용하는 것으로 알려져 왔다 Originally it varies from animal to animal, but in humans there is 44 amino acids of GHRH. The regulation of growth hormone secretion in the human body is a hormone called GHRH which promotes the secretion of growth hormone and somatostatin which inhibits the growth hormone secretion. It has been known to act to secrete
GHRP-6는 생물학적 활성도에 있어서 상기 GHRH 보다 효과는 저조하지만 분자량 크기 면에서는 상당히 압축되어 있는 유용한 합성 펩타이드이다(대한 내분비학회지, 1995, 10(1), 1-9). GHRP-6의 개발 이후 많은 연구자들에 의해 GHRP-6가 GHRH와 동일한 수용체(receptor)에 작용하여 효과를 나타내는 것이 아니라는 보고가 있었고, 이러한 합성화합물인 성장호르몬 분비촉진제들이 경유하는 새로운 수용체의 존재 가능성이 제기되었다(Endocrinology, 1989, 124, 2791). 이러한 가능성은 머크(Merck)사의 연구진에 의해 돼지와 사람의 뇌하수체 만곡형상 복층정중(Arcuate ventro-medial) 부위 그리고 시상하부에 존재하는 성장호르몬 분비촉진제 수용체의 cDNA의 염기서열이 밝혀지면서 사실로 입증되었다(Science, 1996, 273, 974-977). 이러한 사실을 통해 기존에 밝혀진 성장호르몬 분비촉진호르몬과 합성화합물인 성장호르몬 분비촉진제 사이의 상승작용(synergism)이 입증되었으며, 체내에 존재하여 GHRH와 같은 역할을 수행하리라 추측되는 물질의 규명에 더욱 관심이 증가되고 있는 실정이다.GHRP-6 is a useful synthetic peptide that is less effective than GHRH in biological activity but is highly compressed in terms of molecular weight size ( Journal of Endocrinology , 1995, 10 (1), 1-9). Since the development of GHRP-6, many researchers have reported that GHRP-6 does not act on the same receptors as GHRH, and the possibility of the presence of new receptors via these synthetic growth hormone secretagogues. Has been raised ( Endocrinology , 1989, 124, 2791). This possibility is demonstrated by the discovery of the cDNA sequence of growth hormone secretagogue receptors present in the pituitary archromediate and hypothalamus of pigs and humans by Merck researchers. ( Science , 1996, 273, 974-977). This fact proved the synergism between the previously found growth hormone secretagogue and the synthetic compound growth hormone secretagogue, and is more interested in the identification of substances that exist in the body and are expected to play the same role as GHRH. This situation is increasing.
미국 머크사가 개발한 L-692, 429(Science, 1993, 260, 1640-1643)는 선택적으로 성장호르몬을 분비시키는 것으로 알려졌으며, 동물 실험 단계에서도 효과적인 체내 흡수율을 보여주었다. 그러나 인체 실험 결과는 동물의 그것과 다르게 경구 투여시 흡수가 그리 높지 않은 문제점이 있었다. 이에 이러한 문제를 개선한 L-163, 191 이 개발되었고, 이는 기존에 개발되었던 성장호르몬 분비촉진제들의 가장 큰 문제점이었던 경구 흡수율을 높인 화합물로서 개에 경구 투여시 60% 이상의 흡수율을 나타내는 것으로 보고되었고 이를 바탕으로 임상시험이 진행중이다(PNAS, 1995, 92, 7001-7005; Endocrinology, 1996, 137, 5284-5289). 이들 물질에 관한 연구 결과는 뇌하수체를 자극하여 성장호르몬을 분비시키는 물질 등이 성장호르몬 대체제로서 임상적으로 유용하게 사용될 수 있음을 시사하고 있는 반면, 새로운 성장호르몬 분비촉진제를 개발하는 것이 용이하지 않다는 것을 보여준다.L-692, 429 ( Science , 1993, 260, 1640-1643), developed by Merck, USA, has been shown to selectively secrete growth hormone, and has been shown to have an effective body absorption rate even in animal testing. However, the results of human experiments, unlike that of animals had a problem that the absorption is not very high when administered orally. Therefore, L-163, 191, which improved these problems, was developed, which is a compound that increased the oral absorption rate, which is the biggest problem of the growth hormone secretagogues that have been developed previously, and has been reported to have an absorption rate of more than 60% when orally administered to dogs. Clinical trials are underway ( PNAS , 1995, 92, 7001-7005; Endocrinology , 1996, 137, 5284-5289). The results of these studies suggest that substances that stimulate the pituitary gland to secrete growth hormone may be useful clinically as growth hormone replacements, while developing new growth hormone secretagogues is not easy. Shows.
이러한 연구의 일환으로 인체 내에 무해한 천연물 추출물을 이용하여 성장호르몬 분비촉진 역할을 하는 물질을 찾는 연구가 진행되고 있다. 그 예로 황기 뿌리의 알콜 추출물 그리고 7-하이드록시-4'-메톡시-이소플라본(7-hydroxy-4'-methoxy-isoflavone, formononetin) 및 스티그마스트-4-엔-6β-올-3-온(stigmast-4-en-6β-ol-3-one) 등이 성장호르몬 분비를 자극하는 활성이 있음이 본 발명자들에 의해 확인된 바 있고(대한민국 특허등록 제 257840호 및 제 251519호; Kim, J. S. and Kim, C. S., Kor. J. Pharmacogn., 1997, 28(2), 75-79; Kim, J. S. et al., Kor. J. Pharmacogn., 1996, 27(4), 336-341), 원지 추출물, 사상자 추출물, 백합 추출물 및 길경 추출물로 이루어진 그룹 중에서 선택된 1종 이상의 추출물을 함유하는 성장호르몬 분비촉진 조성물에 관한 것(대한민국 특허출원 제 1998-0053921호), 천연 생약재로부터 성장호르몬 분비 자극인자를 추출하는 방법 및 수용성 속단 추출물(대한민국 특허출원 제 1998-014589호)과 글리코알카로이드(glycoalkaloids) 계열의 아스퍼로사포닌 H1(asperosaponin H1)의 성장호르몬 분비촉진인자(대한민국 특허출원 제 1998-014590호)에 대한 연구가 보고되어 있다.As part of such research, researches on finding substances that promote growth hormone secretion using natural extracts that are harmless to the human body are being conducted. Examples include alcoholic extracts of Astragalus root and 7-hydroxy-4'-methoxy-isoflavone, formononetin and stigmas-4-en-6β-ol-3-one (stigmast-4-en-6β-ol-3-one) and the like have been confirmed by the present inventors to stimulate growth hormone secretion (Korean Patent Nos. 257840 and 251519; Kim, JS and Kim, CS, Kor. J. Pharmacogn ., 1997, 28 (2), 75-79; Kim, JS et al., Kor. J. Pharmacogn. , 1996, 27 (4), 336-341), Regarding the growth hormone secretagogue composition containing one or more extracts selected from the group consisting of extracts from the ground, extracts from the dead, extracts from lilies, and gilyeong extracts (Korean Patent Application No. 1998-0053921), growth hormone secretion stimulating factor from natural herbal medicines Method and extract of water-soluble fast extract (Korean Patent Application No. 1998-014589) and glycoalkaloids A buffer saponin H1 growth hormone secretion stimulators of (asperosaponin H1) has been reported studies on (Republic of Korea Patent Application No. 1998-014590 No.).
둥굴레는 우리나라에 자생하는 다년생 초본으로 옥죽(Polygonatum odoratum var. pluriflorum Ohwi)으로 생약으로 근경을 사용하며 옥죽(玉竹, Polygonati Rhizoma)이라 한다. 옥죽의 이명은 지절(地節), 황지(黃芝), 여위(女委), 위유, 죽절황(竹節黃), 산옥죽(山玉竹) 등으로 불리운다.Dungole is a perennial herb that grows in Korea and is used as a herbal medicine as polygonatum odoratum var.pluriflorum Ohwi. It is called jade bamboo (玉竹, Polygonati Rhizoma). Jade's tinnitus is known as Jijeol (地 節), Hwangji (黃 芝), skinny (위), stomach milk, bamboo jeolhwang (竹節 黃), Sanokjuk (山 玉竹).
우리나라에서는 옥죽의 기원식물로 함께 쓰이는 것은 용둥굴레, 통둥굴레, 왕둥굴레, 죽대등이 있다. 둥굴레는 다년성의 초본으로서 초고는 30-60 ㎝ 내외에 이르며 줄기는 직립하지 않고 포물선형으로 뻗고 외대이다. 잎은 줄기의 중앙부터 위쪽에 호생하며 잎자루는 없고 잎몸은 혁질에 가까워 뻣뻣하고 길이는 6-12 ㎝, 너비는 3-6 ㎝이다. 둥굴레의 근경은 가을 또는 이른 봄에 채취하여 줄기와 수염뿌리를 제거하고 응달에서 말리거나 아니면 수증기로 쪄서 햇볕에 말려서 약용한다. In Korea, used as the origin of jade porridge, there are dongdonggore, tongdonggore, dongdonggore, and bamboo stand. Dungole is a perennial herb, super high, about 30-60 ㎝, with stems extending in a parabolic shape without standing upright. Leaves regenerate from the center of the stem to the upper part, without petioles, the leaf body is close to the leather, stiff, 6-12 ㎝ long, and 3-6 ㎝ wide. The root canal is harvested in autumn or early spring to remove stems and roots, dried in the shade or steamed in the sun and medicated in the sun.
둥굴레의 성분은 강심배당체인 콘발라마린(convallamarin), 콘발라린(convallarin), 점액으로는 폴리고나툼-프럭탄(polygonatum-fructan)이 함유되어 있다. Its components include convallamarin (convallamarin), convallarin (convallarin), and polygonatum-fructan (mucopolysaccharide) as mucus.
둥굴레의 약효는 근경이 소염성 자양, 강장약으로 병후 허약자, 해소 천식, 다한, 다뇨, 유정, 당뇨병에 따른 구갈에 사용한다. 둥굴레는 무독하고 맛은 달다. 수치법으로 껍질을 벗기고 밀수에 찐 후에 말려서 사용한다. 특히 자양강장제로 사용할 때에 수치된 둥굴레를 사용한다. 중국에서는 둥굴레의 추출물이 과혈당에 대해 유효하게 작용하여 혈당을 강하시키기 때문에 항당뇨제로 이용되고 있으며 국내의 연구에 의해 그 유효성분의 분리가 진행중에 있다. The drug's medicinal roots are anti-inflammatory nourishment and tonic medicines. It is poisonous and tastes sweet. Peel with a numerical method, steamed and smuggled before use. Especially when using as a nutritious tonic, use a rounded bridle. In China, the extract of Hunggoulee has been used as an anti-diabetic agent because it effectively acts on hyperglycemia and lowers blood sugar.
최근 과학적인 연구결과에 의한 둥굴레의 효과를 살펴보면 둥굴레 뿌리의 메탄올 추출물이 쥐에서 1-7 ㎎/㎖에서 농도에 따른 왼쪽 심방의 긴장이 증가되고 cAMP 포스포디이스터라제(phosphodiesterase)를 크게 억제하는 효과(Biological Pharmaceutical Bulletin, 1997, 20(12), 1271-3)를 보였으며 스테로이달 사포닌 POD-Ⅱ(steroidal saponin POD-Ⅱ)가 쥐의 혈청에서 CSF(콜로니 자극 인자)를 유도할 수 있다. 인슐린 무관 당뇨별 모델인 KK-Ay 생쥐에서 둥굴레 뿌리의 메탄올 추출물은 800 ㎎/㎏으로 복강 투여시 4시간 후에 혈당치를 감소시켰다(Biological Phamaceutical Bulletin, 1995, 18, 1605-6).According to the results of recent scientific studies, the effects of the roundworm were shown by the methanol extract of the round root, which increases the tension of the left atrium at concentrations of 1-7 mg / ml in rats and greatly inhibits cAMP phosphodiesterase. ( Biological Pharmaceutical Bulletin , 1997, 20 (12), 1271-3) and steroidal saponin POD-II can induce CSF (colony stimulating factor) in rat serum. In KK-Ay mice, an insulin-independent diabetic model, the methanol extract of the round root was reduced to 800 mg / kg after 4 hours of intraperitoneal administration ( Biological Phamaceutical Bulletin , 1995, 18, 1605-6).
또한, 둥굴레 뿌리의 에탄올 추출물에서 사포닌 POD-Ⅱ(saponin POD-Ⅱ), β-시토스테롤(β-sitosterol)을 분리했고 상기 알코올 추출물은 몸 표면에 5% 화상입은 생쥐에서 마크로파지(macrophage)의 탐식작용(phagocytosis)의 퍼센트와 인덱스를 증가시키고, 헤모라이신(hemolysin)과 림포사이트(lymphocyte)의 증식을 증가시켰다(Chung-Kuo Chung Yao Tsa Chin, China J. Chinese Meteria, Medica, 1990, 15, 577-9).In addition, saponin POD-II and β-sitosterol were isolated from the ethanol extracts of the roots, and the alcohol extract was used for phagocytosis of macrophage in 5% burned mice. increased the percentage and index of phagocytosis and increased proliferation of hemolysin and lymphocyte (Chung-Kuo Chung Yao Tsa Chin, China J. Chinese Meteria, Medica, 1990, 15, 577 -9).
이와 같이 여러 가지 효능이 있는 것으로 알려진 둥굴레는 현재까지 다른 생약재와의 혼합물 형태로 주로 차나 음료 및 증류주 형태의 주류로서 제조되어 왔다. 둥굴레를 이용하여 간암의 치료나 예방에 사용하고(US 6074648), 둥굴레 추출물을 차 또는 자양강장제로 사용한다(JP 11343245A2). 또는 처방으로 표백화장품으로 사용하고(JP 11335233A2), 드링크제로도 사용하며 간질환 치료제로 쓰인다. 중국에서는 둥굴레의 다당류를 술에 담그거나 차로 만들어 장수약으로 사용한다(CN 1259349A, CN 1197606A). 또한 복합체로 각기병에 쓰이고(CN 1192363A) 피로회복제로 쓰며(CN 1189971A), 남성불임이나 다이어트에 사용된다.As described above, the doungle is known to have various effects, and has been produced as a liquor mainly in the form of a tea, a beverage, and a distilled liquor in a mixture with other herbal medicines. It is used for the treatment or prevention of liver cancer using the hulling agent (US 6074648), and the hulling extract is used as tea or nourishing tonic (JP 11343245A2). It is also used as a bleach cosmetic (JP 11335233A2) as a prescription, as a drink, and as a treatment for liver disease. In China, the polysaccharides of the round ole are immersed or made into tea and used as longevity (CN 1259349A, CN 1197606A). It is also used as a complex in various diseases (CN 1192363A) and as a fatigue remedy (CN 1189971A) and in male infertility or diet.
이에, 본 발명자들은 둥굴레 추출물의 생리학적 활성을 연구한 결과, 둥굴레 추출물이 성장호르몬 분비촉진제로 작용하여 성장호르몬의 생산을 증가시킴을 밝힘으로써 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by revealing that the dongleule extract acts as a growth hormone secretagogue to increase the production of growth hormone as a result of studying the physiological activity of the dongleule extract.
본 발명의 목적은 성장호르몬 분비촉진 활성을 갖는 둥굴레 추출물의 제조방법, 상기 방법에 의해 얻어지는 둥굴레 추출물 및 이를 유효성분으로 함유하는 약학적 조성물 및 건강식품을 제공하는 것이다. It is an object of the present invention to provide a method for producing a extract of Hungle, which has a growth hormone secretagogue activity, a Hungle extract obtained by the above method, and a pharmaceutical composition and health food containing the same as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 둥굴레 추출물의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a manufacturing method of the extract.
또한, 본 발명은 상기 방법에 의해 제조되는 성장호르몬 분비촉진 활성을 갖는 둥굴레 추출물을 제공한다.In addition, the present invention provides a extract of the dongleul having growth hormone secretagogue activity prepared by the above method.
또한, 본 발명은 상기 둥굴레 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for promoting growth hormone secretion containing the extract as an active ingredient.
또한, 본 발명은 상기 둥굴레 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 건강식품을 제공한다.In addition, the present invention provides a growth hormone secretion promoting health food containing the extract as an active ingredient.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 둥굴레 추출물의 제조방법을 제공한다.The present invention provides a method for producing a extract.
구체적으로 본 발명에서는 둥굴레를 알콜 또는 알콜과 물의 혼합용매를 첨가하고 5 내지 40℃에서 침지하여 상기 둥굴레 추출물을 제조하는 방법을 제공한다. 상기에서 알콜 수용액은 10 내지 100%의 에틸알콜(ethyl alcohol), 10 내지 100%의 메틸알콜(methyl alcohol) 및 주정으로 구성된 군으로부터 선택되어 사용될 수 있다.In detail, the present invention provides a method for preparing the dongleul extract by adding a solvent or a mixed solvent of alcohol and water and immersing at 5 to 40 ℃. The aqueous alcohol solution may be selected from the group consisting of 10 to 100% ethyl alcohol (ethyl alcohol), 10 to 100% methyl alcohol (methyl alcohol) and spirits.
또한 본 발명에서는 둥굴레를 산 또는 염기로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합용매를 첨가하여 둥굴레 추출물을 제조하는 방법을 제공한다. 이 때 상기 산 또는 염기는 0.1 내지 2 N의 농도인 것이 바람직하며, 산은 염산, 황산, 질산 및 인산으로 구성된 군으로부터 선택되어 사용될 수 있고 염기는 수산화나트륨 및 수산화칼륨으로 구성된 군으로부터 선택되어 사용될 수 있다. 이 방법에 의하면 당 또는 다른 알킬기 등 여러 가지 치환기와 결합되어 있던 식물의 결합형 화합물이 가수분해되어 둥굴레 추출물에는 식물의 유리된 형태의 화합물로 포함된다. 상기에서 알콜 수용액은 10 내지 100%의 에틸알콜(ethyl alcohol), 10 내지 100%의 메틸알콜(methyl alcohol) 및 주정으로 구성된 군으로부터 선택되어 사용될 수 있다.In another aspect, the present invention provides a method for producing a extract of the donggulle by hydrolyzing and neutralizing the donggolre with an acid or a base, and then adding an alcohol or a mixed solvent of alcohol and water. At this time, the acid or base is preferably in a concentration of 0.1 to 2 N, the acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid and the base may be selected from the group consisting of sodium hydroxide and potassium hydroxide. have. According to this method, the bound compound of the plant, which has been bound to various substituents such as sugar or other alkyl groups, is hydrolyzed, and the extract is included as a free form of the plant. The aqueous alcohol solution may be selected from the group consisting of 10 to 100% ethyl alcohol (ethyl alcohol), 10 to 100% methyl alcohol (methyl alcohol) and spirits.
또한, 본 발명은 상기 방법에 의해 제조되는 성장호르몬 분비촉진 활성을 갖는 둥굴레 추출물을 제공한다.In addition, the present invention provides a extract of the dongleul having growth hormone secretagogue activity prepared by the above method.
본 발명자들은 본 발명의 둥굴레 추출물이 성장호르몬 분비 촉진 활성을 갖는지 확인해 보았다. 먼저, 생후 4-5 주령의 스프래그-다우리(Sprague-Dawley rat) 랫트로부터 무균 조작하에 뇌하수체를 꺼낸 뒤 약하게 세척하고 잘게 분쇄하여 뇌하수체 세포(pituitary cell)를 분리하였다. 상기에서 분리한 뇌하수체 세포에 본 발명의 둥굴레 추출물을 가하였으며, 비교군으로는 성장호르몬 분비의 기준 물질인 랫트 성장호르몬 분비인자(rat GRF, Bachem Co., Torrance, CA, U.S.A.)를 가한 후에 37℃에서 배양하였다. 배양한 후 원심분리하여 그 상등액을 분리하였으며, 쥐 성장호르몬 RIA 키트를 사용하여 성장호르몬의 양을 측정하였다. The present inventors confirmed whether the extract of the present invention has growth hormone secretagogue promoting activity. First, pituitary cells were removed from Sprague-Dawley rats, 4-5 weeks of age, under aseptic manipulation, gently washed and crushed to separate pituitary cells. The rat's gourd extract of the present invention was added to the pituitary cells isolated above, and the rats added rat growth hormone secretion factor (rat GRF, Bachem Co., Torrance, CA, USA) as a reference substance for growth hormone secretion. Incubated at ℃. After incubation, the supernatant was separated by centrifugation, and the amount of growth hormone was measured using a rat growth hormone RIA kit.
그 결과, 본 발명의 둥굴레 추출물은 뇌하수체 세포에 작용하여 성장호르몬의 분비를 촉진시키며, 아울러 비교군으로 사용한 랫트 성장호르몬 분비인자보다 성장호르몬은 분비촉진 효과가 월등히 뛰어남을 확인하였다(표 1 참조).As a result, the extract of the present invention acts on the pituitary cells to promote the secretion of growth hormone, and it was confirmed that the growth hormone was much better in promoting the secretion than the rat growth hormone secretion factor used as a comparison group (see Table 1 ). .
또한, 동물모델을 이용한 성장호르몬 분비촉진 실험 결과, 둥굴레 추출물은 시험관(in vitro) 뿐만 아니라 생체내(in vivo)에서 성장호르몬을 강력하게 증가시키는 것으로 나타났다(표 2 참조).In addition, growth hormone secretion experiments using animal models showed that the extract was strongly increased growth hormone in vitro ( in vitro ) as well as in vivo (see Table 2 ).
또한, 본 발명은 상기 둥굴레 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for promoting growth hormone secretion containing the extract as an active ingredient.
본 발명의 성장호르몬 분비촉진용 약학적 조성물은 상기 둥굴레 추출물을 유효 성분으로 함유한다. 상기 둥굴레 추출물은 임상 투여 시에 경구 또는 비경구로 투여가 가능하며 일반적인 의약품 제제의 형태로 사용될 수 있다. 즉, 본 발명의 둥굴레 추출물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 둥굴레 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제가 포함된다. 비수성용제와 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다. The pharmaceutical composition for promoting growth hormone secretion of the present invention contains the extract of Aspergillus as an active ingredient. The doungle extract can be administered orally or parenterally during clinical administration and can be used in the form of a general pharmaceutical formulation. That is, the extract of the present invention can be administered in various oral and parenteral formulations during actual clinical administration, and when formulated, diluents such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants that are commonly used, or Formulated using excipients. Solid preparations for oral administration include tablets, pills, powders, granules and capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose and gelatin, etc. Mix is prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.
투약 단위는, 예를 들면 개별 투약량의 1, 2, 3 또는 4배를 함유하거나 또는 1/2, 1/3 또는 1/4배를 함유할 수 있다. 개별 투약량은 바람직하기로는 유효 약물이 1회에 투여되는 양을 함유하며, 이는 통상 1일 투여량의 전부, 1/2, 1/3 또는 1/4배에 해당한다.Dosage units may contain, for example, one, two, three or four times the individual dosage, or they may contain 1/2, 1/3 or 1/4 times. The individual dosage preferably contains an amount in which the effective drug is administered at one time, which usually corresponds to all, 1/2, 1/3 or 1/4 times the daily dose.
둥굴레 추출물의 유효용량은 0.1 내지 40 ㎎/㎏이고, 바람직하기로는 0.4 내지 4 mg/kg이며, 하루 1-6 회 투여될 수 있다. The effective dose of the extract is 0.1-40 mg / kg, preferably 0.4-4 mg / kg, and can be administered 1-6 times a day.
본 발명의 둥굴레 추출물을 마우스에 경구 투여, 복강 내 투여시 및 피하 주사시의 독성 실험을 수행한 결과, 복강 내 투여 및 정맥 주사 독성 실험에 의한 50% 치사량(LD50)은 적어도 물 추출물 112.5 g/kg 이상인 안전한 물질로 판명되었다.As a result of conducting oral administration, intraperitoneal administration and subcutaneous injection of the dongleule extract of the present invention to mice, 50% lethal dose (LD 50 ) by intraperitoneal administration and intravenous toxicity test was at least 112.5 g of water extract. It turns out to be a safe substance that is more than / kg
또한, 본 발명은 둥굴레 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 건강식품을 제공한다.In addition, the present invention provides a growth hormone secretion-promoting health food containing the extract as an active ingredient.
본 명세서에서 건강식품이란 일반 식품에 둥굴레 추출물을 첨가함으로써 일반 식품의 기능을 향상시킨 식품이며, 둥굴레 추출물을 일반식품에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조할 수 있다. 이를 섭취할 경우 건강상 특정한 효과를 가져오고, 일반 약품과는 달리 식품을 원료로 하였기 때문에 약품의 장기복용시 발생할 수 있는 부작용 등이 없는 장점이 있다.In the present specification, the health food is a food that has improved the function of the general food by adding the extract to the general food, the extract can be added to the general food, or can be prepared by encapsulation, powdered, suspension and the like. When ingested, it brings a specific effect on health, and unlike the general medicine because the food is a raw material has the advantage that there is no side effect that can occur during long-term use of the drug.
본 발명의 둥굴레 추출물을 식품 첨가물로 사용할 경우, 상기 둥굴레 추출물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 둥굴레 추출물을 식품 또는 음료의 제조시에 원료에 대하여 0.0001 내지 10 중량%, 바람직하게는 0.1 내지 5 중량%의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다. 또한, 본 발명의 건강식품은 상기 약학적 조성물로의 용도시 측정된 독성 범위내의 둥굴레 추출물을 함유한다.When the extract of the present invention is used as a food additive, the extract is added as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The blending amount of the active ingredient can be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment). In general, the extract can be added in an amount of 0.0001 to 10% by weight, preferably 0.1 to 5% by weight based on the raw materials in the manufacture of food or beverage. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be below the above range. In addition, the health food of the present invention contains an extract of the dongle in the range of toxicity measured when used in the pharmaceutical composition.
상기 식품의 종류에는 특별한 제한은 없다. 상기 둥굴레 추출물을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있다. 구체적으로, 둥굴레 추출물을 함유하는 건강 식품으로는 둥굴레를 주성분으로 만든 즙, 차, 젤리, 쥬스 등의 건강식품 및 기호품을 들 수 있으며, 소염성 자양, 강장약 등을 목적으로 하는 민간요법제 등을 들 수 있다. There is no particular limitation on the kind of food. Examples of foods to which the extract is added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, teas, drinks Alcoholic beverages and vitamin complexes. Specifically, the health food containing the extract is a health food and favorite products such as juice, tea, jelly, juice made with the main ingredient, and folk remedies for the purpose of anti-inflammatory nutrition, tonic medicines, etc. Can be mentioned.
이하, 본 발명을 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.
<실시예 1> 둥굴레 추출물의 제조 1<Example 1> Preparation of the extract
둥굴레 건조물 분말 50 g을 70% 메탄올 수용액 500 ㎖에 첨가하여 실온에서 2일 동안 교반시켰다. 교반 과정을 거쳐 얻어진 용액을 거름종이로 여과한 후 감압 농축하여 메탄올을 제거한 뒤 동결 건조하여 수분을 제거하여 본 발명의 둥굴레 추출물을 제조하였다.50 g of dry product powder was added to 500 ml of 70% aqueous methanol solution and stirred at room temperature for 2 days. The solution obtained through the stirring process was filtered through a filter paper, concentrated under reduced pressure to remove methanol, and then lyophilized to remove moisture to prepare a extract of the present invention.
<실시예 2> 둥굴레 추출물의 제조 2<Example 2> Preparation 2 of the extract
둥굴레 건조물 분말 0.1 g을 1 N HCl 수용액 1 ㎖에 넣고 100℃에서 2시간 동안 반응시켰다. 2시간 동안 가수분해시킨 뒤 중화한 후 상기 반응액을 동결건조로 수분을 제거한 후 실시예 1과 동일하게 본 발명의 둥굴레 추출물을 제조하였다.0.1 g of dry powder of dried products was put in 1 ml of 1 N HCl aqueous solution and reacted at 100 ° C. for 2 hours. After neutralizing for 2 hours and neutralizing, the reaction solution was lyophilized to remove water, and thus, the extract of the present invention was prepared in the same manner as in Example 1.
<제제예 1> 주사액제의 제조방법Preparation Example 1 Preparation of Injection Solution
유효성분 10 ㎎을 함유하는 주사액제는 다음과 같은 방법으로 제조하였다. Injection solution containing 10 mg of the active ingredient was prepared by the following method.
둥굴레 추출물 1 g, 염화나트륨 0.6 g 및 아스코르브산 0.1 g을 증류수에 용해시켜서 100 ㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.100 g of 1 g of a hulling extract, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.
상기 주사액제의 구성성분은 다음과 같다. The components of the injection solution are as follows.
둥굴레 추출물 1 g1 g of coniferous extract
염화나트륨 0.6 g0.6 g sodium chloride
아스코르브산 0.1 g0.1 g of ascorbic acid
증류수 정량Distilled Water Determination
<제제예 2> 시럽제의 제조방법Preparation Example 2 Preparation of Syrup
본 발명의 둥굴레 추출물을 유효성분 2% (중량/부피)로 함유하는 시럽은 다음과 같은 방법으로 제조한다. Syrup containing the extract of the present invention as an active ingredient 2% (weight / volume) is prepared by the following method.
둥굴레 추출물, 사카린, 당을 온수 80 g에 용해시켰다. 이 용액을 냉각시킨 후, 여기에 글리세린, 향미료, 에탄올, 소르브산 및 증류수로 이루어진 용액을 제조하여 혼합하였다. 이 혼합물에 물을 첨가하여 100 ㎖가 되게 하였다. Dongle extract, saccharin and sugar were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, spices, ethanol, sorbic acid and distilled water was prepared and mixed therein. Water was added to this mixture to 100 ml.
상기 시럽제의 구성성분은 다음과 같다.The components of the syrup are as follows.
둥굴레 추출물 2 g2 g of dongleule extract
사카린 0.8 gSaccharin 0.8 g
당 25.4 g25.4 g per
글리세린 8.0 gGlycerin 8.0 g
향미료 0.04 g0.04 g of spices
에탄올 4.0 gEthanol 4.0 g
소르브산 0.4 g0.4 g of sorbic acid
증류수 정량Distilled Water Determination
<제제예 3> 정제의 제조방법Preparation Example 3 Manufacturing Method
유효성분 15 ㎎이 함유된 정제는 다음과 같은 방법으로 제조한다.A tablet containing 15 mg of active ingredient is prepared by the following method.
둥굴레 추출물 250 g, 락토오스 175.9 g, 감자전분 180 g 및 콜로이드성 규산 32 g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160 g, 활석 50 g 및 스테아린산 마그네슘 5 g을 첨가해서 얻은 혼합물을 정제로 만들었다. It was mixed with 250 g of a hulling extract, 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.
상기 정제의 구성성분은 다음과 같다. The components of the tablet are as follows.
둥굴레 추출물 250 g250 g of gorilla extract
락토오스 175.9 gLactose 175.9 g
감자전분 180 g180 g potato starch
콜로이드성 규산 32 g32 g of colloidal silicic acid
10% 젤라틴 용액10% gelatin solution
감자전분 160 gPotato Starch 160 g
활석 50 g50 g of talc
스테아르산 마그네슘 5 g5 g of magnesium stearate
<제제예 4> 식품 및 음료의 제조방법Preparation Example 4 Manufacturing Method of Food and Beverage
본 발명자들은 둥굴레 추출물을 유효성분으로 함유하는 식품 또는 음료 조성물을 하기와 같이 제조하였다.The present inventors prepared a food or beverage composition containing the extract as an active ingredient as follows.
<4-1> 비스켓의 제조<4-1> Preparation of Biscuits
박력1급 88 ㎏Force Class 1 88 kg
중력1급 76.4 ㎏Gravity First Class 76.4 ㎏
정백당 16.5 ㎏16.5 kg per white
식염 2.5 ㎏ 2.5 kg of salt
포도당 2.7 ㎏2.7 kg of glucose
팜쇼트닝 40.5 ㎏Palm shortening 40.5 kg
암모 5.3 ㎏5.3 kg of ammo
중조 0.6 ㎏Medium kg 0.6 kg
중아황산나트륨 0.55 ㎏0.55 kg sodium bisulfite
쌀가루 5.0 ㎏Rice flour 5.0 kg
비타민 B1 0.003 ㎏Vitamin B1 0.003 kg
비타민 B2 0.003 ㎏0.003 kg of vitamin B2
밀크향 0.16 ㎏Milk Flavor 0.16 ㎏
물 71.1 ㎏ 71.1 kg of water
전지분유 4 ㎏Whole milk powder 4 kg
대용분유 1 ㎏Substitute powder 1 kg
제일인산칼슘 0.1 ㎏0.1 kg of calcium phosphate
살포염 1 ㎏Spray salt 1 kg
분무유 25 ㎏ 25 kg of spray oil
둥굴레 추출물 0.1 ∼ 0.5 ㎏0.1 kg to 0.5 kg
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 비스켓을 제조하였다. Biscuits were prepared using conventional methods with the above composition and content.
<4-2> 음료의 제조<4-2> Preparation of Beverage
꿀 522 ㎎522 mg of honey
치옥토산아미드 5 ㎎Chioctosanamide 5 mg
니코틴산아미드 10 ㎎Nicotinamide 10 mg
염산리보플라빈나트륨 3 ㎎Riboflavin Sodium Hydrochloride 3 mg
염산피리독신 2 ㎎Pyridoxine hydrochloride 2 mg
이노시톨 30 ㎎Inositol 30 mg
오르트산 50 ㎎Orthoic acid 50 mg
둥굴레 추출물 0.48 ∼ 1.28 ㎎Donguile Extract 0.48-1.28 mg
물 200 ㎖200 ml of water
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 음료를 제조하였다. With the above composition and content, drinks were prepared using conventional methods.
<실험예 1> 둥굴레 추출물을 이용한 성장호르몬 분비촉진 활성실험Experimental Example 1 Growth Hormone Secretion Activity Test
<1-1> 뇌하수체 세포 배양<1-1> Pituitary Cell Culture
생후 4-5 주령의 스프래그-다우리(Sprague-Dawley rat) 랫트로부터 무균 조작하에 뇌하수체를 꺼낸 뒤 콜라게네이즈(collagenase, Gibco co., Grand Island, NY)와 히알루로니데이즈(hyaluronidase, Sigma co., St. Louis, MO)로 처리하여 뇌하수체 세포(rat pituitary cell)를 분리하였다. 분리된 뇌하수체 세포를 10% 말 혈청(horse serum), 2.5% 태아 소 혈청(fetal bovine serum, FBS), 및 항생제를 함유하는 DMEM 배지(Dulbecco's Modified Eagle's medium)에 부유시킨 후 항습 조건(humidified condition, 37℃, 5% CO2)에서 배양하였다.The pituitary gland was removed from Sprague-Dawley rats at 4-5 weeks of age under aseptic manipulation, followed by collagenase (Gibco co., Grand Island, NY) and hyaluronidase (Sigma co). , St. Louis, Mo.) rat rat pituitary cells were isolated. The isolated pituitary cells were suspended in Dulbecco's Modified Eagle's medium containing 10% horse serum, 2.5% fetal bovine serum (FBS), and antibiotics. Incubated at 37 ° C., 5% CO 2 ).
<1-2> 성장호르몬 분비 촉진 활성 실험 <1-2> Growth hormone secretion promoting activity experiment
상기 실험예 <1-1>에서 분리한 뇌하수체 세포를 배양한 후에 시험액에 부유시켰다. 약재를 1 mg/ml 농도로 뇌하수체 세포에 가하였으며, 비교군으로는 성장호르몬 분비의 기준 물질인 랫트 성장호르몬 분비인자(rat GRF, Bachem Co., Torrance, CA, U.S.A.)를 300 nM, 500 nM, 1,000 nM이 되도록 가한 후에 총 부피가 1 ㎖가 되도록 시험액을 가하여 37℃에서 15분간 배양하였다. 배양한 후 원심분리하여 그 상등액을 분리하였으며, 성장호르몬을 측정하기 위하여 -70℃에 보관하였다.The pituitary cells isolated in Experimental Example <1-1> were cultured and then suspended in a test solution. Medicinal herbs were added to pituitary cells at a concentration of 1 mg / ml, and rat growth hormone secretion factors (rat GRF, Bachem Co., Torrance, CA, USA), which are reference substances for growth hormone secretion, were 300 nM and 500 nM. , 1,000 nM was added and the test solution was added to a total volume of 1 ml and incubated at 37 ° C. for 15 minutes. After incubation, the supernatant was separated by centrifugation, and stored at -70 ° C to measure growth hormone.
성장호르몬 측정은 쥐 성장호르몬 RIA 키트(rat GH RIA kit, Amersham, Buckinghamshire, England)를 사용하여 수행하였다. 일정한 양의 125I-표지 성장호르몬과 상기에서 보관한 시험물질에 함유된 성장호르몬은 항 성장호르몬 항체(anti-GH antibody)에 대한 경쟁적인 반응에 의해서 각기 다른 양의 성장호르몬-항체 복합체(GH-Ab complex)를 형성하게 되고 여기에 2차 항체(second antibody)를 가하여 침전시킨 후 침전으로부터 125I의 방사활성도를 측정하였고 그 결과를 하기 표 1에 나타내었다.Growth hormone measurement was performed using a rat growth hormone RIA kit (rat GH RIA kit, Amersham, Buckinghamshire, England). The growth hormone contained in a constant amount of 125 I-labeled growth hormone and the test substance stored in the above was tested by different reactions of the growth hormone-antibody complex (GH) by a competitive response to an anti-GH antibody. -Ab complex) was formed and precipitated by addition of a second antibody, and the radioactivity of 125 I was measured from the precipitate. The results are shown in Table 1 below.
* 비교군으로는 랫트 성장호르몬 분비인자를 사용함.The rat growth hormone secretion factor was used as a comparison group.
그 결과, 상기 표 1에서 알 수 있는 바와 같이 본 발명의 둥굴레 추출물은 뇌하수체 세포에 작용하여 성장호르몬의 분비를 촉진시키며, 아울러 비교군으로 사용한 랫트 성장호르몬 분비인자보다 성장호르몬 분비촉진 효과가 월등히 뛰어남을 확인하였다.As a result, as can be seen in Table 1 , the extract of the present invention acts on the pituitary cells to promote the secretion of growth hormone, and the growth hormone secretion effect is superior to the rat growth hormone secretion factor used in the comparison group. It was confirmed.
<실험예 2> 랫트의 성장호르몬 유발 실험Experimental Example 2 Growth Hormone Induction Rat
8주령의 SD 랫트를 펜토바비탈(pentobarbital) 50 mg/kg 농도로 마취시킨 후 둥굴레 추출물을 건조약재 1 mg/kg 농도로 생리식염수에 용해시켜 랫트의 경정맥에 투여하였으며 대조군으로는 생리식염수를 투여하였다. 꼬리 경정맥으로부터 일정 시간간격으로 채혈한 후 RIA 키트를 사용하여 분비된 성장호르몬을 측정하였다. 혈중 성장호르몬의 농도 측정은 상기 실험예 1과 동일한 방법으로 쥐 성장호르몬 RIA 키트(rat GH RIA kit, Amersham, Buckinghamshire, England)를 사용하여 수행하였다. 일정한 양의 125I-표지 성장호르몬과 상기에서 보관한 시험물질에 함유된 성장호르몬은 항 성장호르몬 항체(anti-GH antibody)에 대한 경쟁적인 반응에 의해서 각기 다른 양의 성장호르몬-항체 복합체(GH-Ab complex)를 형성하게 되고 여기에 2차 항체(second antibody)를 가하여 침전시킨 후 침전으로부터 125I의 방사활성도를 측정하여 표준곡선을 이용하여 해당 농도를 계산하였다.8-week-old SD rats were anesthetized at a concentration of 50 mg / kg of pentobarbital, and the extract was dissolved in physiological saline at a concentration of 1 mg / kg of dry medicine and administered to the jugular vein of the rat. It was. After bleeding from the tail jugular vein at regular intervals, the secreted growth hormone was measured using the RIA kit. Measurement of the concentration of growth hormone in the blood in the same manner as in Experimental Example 1 Rat growth hormone RIA kit (rat GH RIA kit, Amersham, Buckinghamshire, England) was performed. The growth hormone contained in a constant amount of 125 I-labeled growth hormone and the test substance stored in the above was tested by different reactions of the growth hormone-antibody complex (GH) by a competitive response to an anti-GH antibody. -Ab complex) was formed and precipitated by addition of a second antibody, and then the concentration was calculated using a standard curve by measuring the radioactivity of 125 I from the precipitate.
상기 표 2에서 보는 바와 같이 동물을 이용하여 본 발명의 둥굴레 추출물을 건조약재 1 mg/kg의 농도로 랫트의 경정맥에 투여한 후 꼬리 정맥으로부터 일정 시간 간격으로 채혈하여 분리된 플라스마의 성장호르몬을 측정한 결과 대조군에 비해 약물 투여 30분 후 약 5배 정도의 증가를 보였고 90분 후 7배 정도의 증가를 보였으며 2시간 이내에 둥굴레 추출물의 성장호르몬 분비 촉진 능력이 측정되었다(도 1).As shown in Table 2 above, using the animal's doungle extract of the present invention to the rat jugular vein at a concentration of 1 mg / kg of dry medicinal herbs and collected blood at regular intervals from the tail vein to measure the growth hormone of plasma isolated As a result, compared with the control group, the drug showed an increase of about 5 times after 30 minutes of drug administration and an increase of 7 times after 90 minutes, and the growth hormone secretion ability of the extract was measured within 2 hours ( FIG. 1 ).
<실험예 3> 랫트에 대한 경구투여 급성 독성실험Experimental Example 3 Oral Acute Toxicity in Rats
6주령의 특정병원체부재(specific pathogen-free, SPF) SD계 랫트를 사용하여 급성독성실험을 실시하였다. 군당 2 마리씩의 동물에 본 발명의 둥굴레 추출물을 각각 0.5% 메틸셀룰로즈 용액에 현탁하여 1 g/㎏/㎖의 용량으로 1회 단회 경구투여 하였다. 시험물질 투여 후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다.Acute toxicity test was performed using 6-week-old specific pathogen-free (SPF) SD rats. Two animals per group were suspended in a 0.5% methyl cellulose solution, respectively, in the roundworm extract of the present invention and administered once orally at a dose of 1 g / kg / ml. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities.
그 결과, 시험물질을 투여한 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. 이상의 결과, 본 발명의 둥굴레 추출물은 모두 랫트에서 2 g 추출물/㎏까지 독성변화를 나타내지 않으며 경구 투여 최소치사량(LD50)은 추출물 10 g/kg 이상에서 죽지 않는 안전한 물질로 판단되었다.As a result, no significant clinical symptoms or dead animals were noted in all animals treated with the test substance, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. As a result, all of the extracts of the present invention do not show a toxicity change up to 2 g extract / kg in rats and the minimum lethal dose (LD 50 ) was determined to be a safe substance that does not die at more than 10 g / kg extract.
상기에서 살펴본 바와 같이, 본 발명의 둥굴레 추출물은 매우 높은 성장호르몬 분비촉진 활성을 나타내고 이 추출물의 원료인 둥굴레가 오래 동안 사용되어온 인체에 무해하고 흡수율이 좋은 천연약재이므로 성장호르몬과 관련된 각종 질환의 치료 및 예방에 유용하게 사용될 수 있다.As described above, the extract of the present invention exhibits a very high growth hormone secretion activity and the treatment of the various diseases related to growth hormone because the extract is harmless to humans and has good absorption rate. And useful for prevention.
도 1은 본 발명의 둥굴레 추출물을 랫트의 경정맥에 투여한 후 꼬리 정맥으로부터 일정 시간 간격으로 성장호르몬을 측정한 것을 그래프로 나타낸 것이다. 1 is a graph showing the growth hormone measured at regular time intervals from the tail vein after administration of the extract of the present invention to the rat jugular vein.
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