KR100497947B1 - Extract of herb for promoting release of growth hormone - Google Patents
Extract of herb for promoting release of growth hormone Download PDFInfo
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- KR100497947B1 KR100497947B1 KR10-2002-0035767A KR20020035767A KR100497947B1 KR 100497947 B1 KR100497947 B1 KR 100497947B1 KR 20020035767 A KR20020035767 A KR 20020035767A KR 100497947 B1 KR100497947 B1 KR 100497947B1
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- South Korea
- Prior art keywords
- growth hormone
- extract
- alcohol
- present
- water
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
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- A61K36/8968—Ophiopogon (Lilyturf)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
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- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
본 발명은 맥문동(Liriopis Tuber) 추출물의 제조방법, 상기 방법에 의해 얻어지는 맥문동 추출물 및 이를 포함하는 약학적 조성물 및 건강식품에 관한 것으로서, 보다 구체적으로는 맥문동을 알콜 또는 알콜과 물의 혼합 용매를 첨가하거나 산 또는 염기 용액으로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합 용매를 첨가하여 추출되는 맥문동 추출물의 제조방법, 상기 방법에 의해 얻어지는 맥문동 추출물 및 이를 유효성분으로 포함하는 약학적 조성물 및 건강식품에 관한 것이다. 본 발명의 맥문동 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 producing Liriopis Tuber extract, to the extract obtained by the method, and to pharmaceutical compositions and health foods comprising the same, more specifically, to add the alcohol or a mixed solvent of alcohol and water Method for preparing ganmundong extract extracted by hydrolyzing and neutralizing with an acid or base solution and adding alcohol or a mixed solvent of alcohol and water, ganmundong extract obtained by the above method and a pharmaceutical composition and health food comprising the same as an active ingredient It is about. Macmundong extract of the present invention shows a strong growth hormone secretagogue activity and can be used as a growth hormone secretagogue drugs and foods because it is secured as a natural drug.
Description
본 발명은 맥문동(Liriopis Tuber) 추출물의 제조방법, 상기 방법에 의해 얻어지는 맥문동 추출물 및 이를 포함하는 약학적 조성물 및 건강식품에 관한 것으로서, 보다 구체적으로는 맥문동을 알콜 또는 알콜과 물의 혼합 용매를 첨가하거나 산 또는 염기 용액으로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합 용매를 첨가하여 추출되는 맥문동 추출물의 제조방법, 상기 방법에 의해 얻어지는 맥문동 추출물 및 이를 유효성분으로 포함하는 약학적 조성물 및 건강식품에 관한 것이다.The present invention relates to a method for producing Liriopis Tuber extract, to the extract obtained by the method, and to pharmaceutical compositions and health foods comprising the same, more specifically, to add the alcohol or a mixed solvent of alcohol and water Method for preparing ganmundong extract extracted by hydrolyzing and neutralizing with an acid or base solution and adding alcohol or a mixed solvent of alcohol and water, ganmundong extract obtained by the above 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 Method and extract of water-soluble fast extract (Korean Patent Application No. 1998-014589) and glycoalkaloids It promotes secretion of growth hormone by the spur saponin H1 (H1 asperosaponin) factors have been reported studies on (Republic of Korea Patent Application No. 1998-014590 No.).
맥문동(麥門冬, Liriope Tuber)은 맥문아 제비과에 속하는 다년생의 숙근초인 일명 대엽맥문동이라 하는 맥문동(Liriope platyphylla Wanget Tang) 또는 소엽맥문동(Ophiopogon japonicus Ker-Gawler)의 뿌리의 팽대부(膨大部)이다. 생약으로는 뿌리에 있는 팽대부를 사용하여 맥문동(麥門冬, Liriope Tuber)이라 한다.Liriope Tuber is the bulge of the root of Liriope platyphylla Wanget Tang or Ophiopogon japonicus Ker-Gawler, a so-called perennial herbaceous genus belonging to the Malmung Swallow family. . The herbal medicine is called Liriope Tuber using the bulge in the root.
대엽맥문동은 우리나라의 제주, 전남, 전북, 경안, 경북, 강원 등지에 널리 분포하여 자생한다. 이 식물의 뿌리의 팽대부는 맥문동(Liriope Radix, Liriope Tuber)이라 해서 약용되는데 비대한 뿌리의 팽대부는 길이 2.5-4 ㎝에 이르고 너비는 1 ㎝ 내외가 된다. 소엽 맥문동은 산지의 수림하에 자생하며 제주, 경남, 경북, 경기 등에 분포한다.The broadleaf vegetation is widely distributed in Korea, Jeju, Jeonnam, Jeonbuk, Gyeongan, Gyeongbuk, and Gangwon. The swelling part of the root of the plant is medicated as Liriope Radix (Liriope Tuber). The bulging part of the bulging root reaches 2.5-4 cm in length and has a width of about 1 cm. The leaf lobe Macmun-dong grows in the forests of mountains and is distributed in Jeju, Gyeongnam, Gyeongbuk, and Gyeonggi.
중국 약전에는 맥동이라 쓰고 마이동(Maidong)으로 불리워지고 소엽맥문동 계열에 속한다. 일본에서는 소엽맥문동(Ophiopogon japonicus)의 뿌리의 팽대부를 맥문동이라 하여 약용하고 있다. 그러나 소엽맥문동의 뿌리 팽대부는 길이가 1 ㎝ 내외이고 너비는 0.5-0.8 ㎝ 이어서 대엽맥문동만은 못하다. 우리나라에서는 대엽맥문동과 소엽맥문동이 다같이 약용되고 있고 이들 두 식물의 잎의 길이, 너비, 뿌리 팽대부의 크기 등에 큰 차이가 있으나 실제에 있어서 생약시장에서 판매되는 생약 맥문동은 이들의 단독 또는 혼합물로서 구성된다.In Chinese Pharmacopoeia, it is called pulsation and is called Maidong and belongs to the leaf lobe gram-mundong family. In Japan, the bulge portion of the root of Ophiopogon japonicus is medicated as pulmonary sinus. However, the root bulge of lobular vein sinus is about 1 ㎝ long and 0.5-0.8 ㎝ in width, so it is not only lobe pulmonary sinus. In Korea, both broadleaf vegetation and leaflet vegetation are medicinal, and there is a big difference in the length, width, and size of root bulge of these two plants. do.
맥문동의 화학성분은 오피오포곤 아미드Ⅵ(Ophiopogon amide Ⅵ), 5,7-디하이드록시-6-포밀-8-메틸-3-(3,4-메틸렌디옥시벤질)크로만-4-원 (5,7-Dihydroxy-6-formyl-8-methyl-3-(3,4-methylen dioxybenzyl)chroman-4-one), 아제티딘-2-카르복실릭산(Azetidine-2-carboxylic acid), 비세닌 2(Vicenin 2), 튜리파닌(Tulipanin), 6-알데히도-아이소오피오포고논 A(6-Aldehydo-isoophiopogonone A), 6-알데히도-아이소오피오포고논 B(6-Aldehydo-isoophiopogone B), 6-알데히도-오피오포고논 A(6-Aldehydo-ophiopogonone A), 오피오포곤(Ophiopogon), 호모아이소플라보노이드 Ⅰ(homoisoflavonoid Ⅰ), 오피오포곤 호모아이소플라보노이드 Ⅱ(Ophiopogon homoisoflavonoid Ⅱ), 오피오포곤 호모아이소플라보노이드 Ⅲ(Ophiopogon homoisoflavonoid Ⅲ), 오피오포곤 호모아이소플라보노이드 Ⅳ(Ophiopogon homoisoflavonoid Ⅳ), 오피오포곤 호모아이소플라보노이드 Ⅴ(Ophiopogon homoisoflavonoid Ⅴ), 오피오포고나논 A(Ophiopogonanone A), 메틸오피오포고나논 A(Methylophiopogonanone A), 메틸 오피오포고나논 B(Methyl ophiopogonanone B), 다우코스테롤(Daucosterol), 7-O-β-D-글루코피래노실-보르네올(7-O-β-D-glucopyranosyl-borneol), 7-O-α-L-아라비노푸마노실(1-6)-β-D-글루코피래노실 보르네올(7-O-α-L-Aravinofuranosyl(1-6)-β-D-glucopyranosylborneol), 오피오포고닌 A(Ophiopogonin A), 오피오포고닌 B(Ophiopogonin B), 오피오포고닌 D(Ophiopogonin D), 오피오포고닌 B'(Ophiopogonin B'), 오피오포고닌 C(Ophiopogon C), 오피오포고닌 C'(Ophiopogonin C'), 오피오포고닌 D'(Ophiopogonin D'), 3-O-α-L-람노피래노실(1-2)-β-D-글루코피래노실오피오제닌(3-O-α-L-Rhamnopyranosyl(1-2)-β-D-glucopyranosylophiogenin) 등이 있다. The chemical composition of Macmundong is Opiopogon amide VI, 5,7-dihydroxy-6-formyl-8-methyl-3- (3,4-methylenedioxybenzyl) chroman-4-one. (5,7-Dihydroxy-6-formyl-8-methyl-3- (3,4-methylen dioxybenzyl) chroman-4-one), Azetidine-2-carboxylic acid, bise Vicenin 2, Tulipinin, 6-Aldehydo-isoophiopogonone A (6-Aldehydo-isoophiopogonone A), 6-Aldehydo-isoopiopogonone B (6-Aldehydo-isoophiopogone B 6-Aldehydo-ophiopogonone A, Opiopogon, Homoisoflavonoid I, Opiopogon homoisoflavonoid II, Opiopogon homoisoflavonoid II, Opiopogon homoisoflavonoid II Opiopogon homoisoflavonoid III, Opiopogon homoisoflavonoid IV, Opiopogon homoisoflavonoid V homoisoflavonoid Ⅴ), Opiopogonanone A, Methylophiopogonanone A, Methyl ophiopogonanone B, Dacosterol, 7-O-β- 7-O-β-D-glucopyranosyl-borneol, 7-O-α-L-arabinofumanosyl (1-6) -β-D-glucopyranosyl boron Neool (7-O-α-L-Aravinofuranosyl (1-6) -β-D-glucopyranosylborneol), Opiopogonin A, Opiopogonin B, Opiopogonin D , Opiopogonin B ', Opiopogonin C, Opiopogonin C', Opiopogonin D ', 3-O-α-L Ramponopyranosyl (1-2) -β-D-glucopyranosyl opiogenin (3-O-α-L-Rhamnopyranosyl (1-2) -β-D-glucopyranosylophiogenin) and the like.
맥문동의 약효는 점활성소염, 백일해, 이뇨, 진해, 심신불안, 거담, 자양강장으로 유명하게 쓰이고 있다. 대표적인 동양의약의 처방은 맥문동탕이 있어 마른기침, 목이 쉬었을 때, 가래가 몹시 점액성을 나타낼 때, 피부건조 등에 쓰인다. Macmundong's medicinal effect is viscous anti-inflammatory, whooping cough, diuresis, Jinhae, mind and body anxiety, expectoration, nourishing tonic is famous. Representative oriental medicine prescription is Mcmundongtang, so dry cough, when the neck is restless, sputum is very mucus, it is used for skin drying.
최근 과학적인 연구결과에 의한 구기자의 효과를 살펴보면 림프구에 대한 마이토젠으로의 역할과 항종양 작용을 하는 렉틴(lectin) 성분이 함유(Yakhak Hoeji, 1996, 40(4), 387-393)되어 있으며 수술 후의 골원성 육종(osteogenic sarcoma) 환자의 화학치료(chemotherapy)와 병행하여 투여한 생약재 조성물이 독성과 부작용을 줄이는 효과가 있음이 보고되고 있다(Zhongguo Zhhong Xi Yi Jie Za Zhi, 1993, 13(3), 150-2).According to the recent scientific results, the effect of goji berry contains lectin, which acts as a mitogen for lymphocytes and has antitumor effects (Yakhak Hoeji, 1996, 40 (4), 387-393). It has been reported that herbal compositions administered in combination with chemotherapy in patients with osteogenic sarcoma after surgery have the effect of reducing toxicity and side effects (Zhongguo Zhhong Xi Yi Jie Za Zhi, 1993, 13 (3). ), 150-2).
이와 같이 여러 가지 효능이 있는 것으로 알려진 맥문동은 현재까지 다른 생약재와의 혼합물 형태로 제조되어 왔다. 맥문동을 이용하여 스포츠 과학 인삼제품 및 그 제조방법(등록번호 211718), 생약추출물을 함유한 구강위생 증진용 조성물(1998, 6. 5), 순환계용 약제 조성물 및 그의 제조방법(등록번호 249934) 및 당뇨병 치료제 및 생약 유래식 이성 섬유의 제조 방법(등록번호 053436)이 있고 국외특허는 우황청심환의 함유성분(US 5190757, US 5164184, US 5133964), 동맥경화증에 사용되는 복합제(JP 104886A2)등이 있으며, 복합제로 노화억제술도 만들고 있다.This is known to have a variety of efficacy of munmundong until now has been prepared in the form of a mixture with other herbal medicines. Sports scientific ginseng products and its manufacturing method (registration No. 211718), the composition for enhancing oral hygiene using herbal extracts (1998, 6. 5), pharmaceutical composition for circulatory system and its preparation method (Registration No. 249934) There is a method for producing diabetic drugs and herbal medicine-derived heterogeneous fiber (Registration No. 053436), and foreign patents include components of whey blue cheongsimhwan (US 5190757, US 5164184, US 5133964), and a combination agent (JP 104886A2) used for atherosclerosis, Anti-aging is also being made with a combination.
이에, 본 발명자들은 맥문동 추출물의 생리학적 활성을 연구한 결과, 맥문동 추출물이 성장호르몬 분비촉진제로 작용하여 성장호르몬의 생산을 증가시킴을 밝힘으로써 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by studying the physiological activity of the extracts, the results revealed that the extract increases the production of growth hormone by acting as a growth hormone secretagogue.
본 발명의 목적은 성장호르몬 분비촉진 활성을 갖는 맥문동 추출물의 제조방법, 상기 방법에 의해 얻어지는 맥문동 추출물 및 이를 유효성분으로 함유하는 약학적 조성물 및 건강식품을 제공하는 것이다. SUMMARY OF THE INVENTION An object of the present invention is to provide a method for preparing extracts of Macmundong having growth hormone secretagogue activity, extracts obtained by the method, and pharmaceutical compositions and health foods containing the same as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 맥문동 추출물의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method for producing the extract.
또한, 본 발명은 상기 방법에 의해 제조되는 성장호르몬 분비촉진 활성을 갖는 맥문동 추출물을 제공한다.In addition, the present invention provides a wormwood extract having growth hormone secretagogue activity prepared by the above method.
또한, 본 발명은 상기 맥문동 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for promoting growth hormone secretion containing the extract as an active ingredient.
또한, 본 발명은 상기 맥문동 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 건강식품을 제공한다.In another aspect, the present invention provides a growth hormone secretion promoting health food containing the extract as the active ingredient.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 맥문동 추출물의 제조방법을 제공한다.The present invention provides a method for producing the extract.
구체적으로 본 발명에서는 맥문동을 알콜 또는 알콜과 물의 혼합용매를 첨가하고 5 내지 40℃에서 침지하여 상기 맥문동 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.Specifically, the present invention provides a method for preparing the pulmonary tract extract by adding ganmundong to alcohol or a mixed solvent of alcohol and water and immersing at 5 to 40 ° C. 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 맥문동을 산 또는 염기로 가수분해하고 중화한 후 알콜 또는 알콜과 물의 혼합용매를 첨가하여 맥문동 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 맥문동 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 preparing the extract of McMoon Dong by hydrolyzing and neutralizing the pulse moon dong 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 bonded to various substituents such as sugar or other alkyl groups, is hydrolyzed, and the extract of Macmundong is included as a compound of the 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 맥문동 추출물을 제공한다.In addition, the present invention provides a wormwood extract having growth hormone secretagogue activity prepared by the above method.
본 발명자들은 본 발명의 맥문동 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 맥문동 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 munmundong has growth hormone secretagogue 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 pulmonary tract extract of the present invention was added to the pituitary cells isolated from the above, and after the rat growth hormone secretion factor (rat GRF, Bachem Co., Torrance, CA, USA), which is a reference substance for growth hormone secretion, was added, 37 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 맥문동 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 mammundong extract of the present invention acted on the pituitary cells to promote the secretion of growth hormone, and the growth hormone secretion was much superior to the rat growth hormone secretion factor used as a comparison group was confirmed that the effect of promoting the secretion was excellent (see Table 1 ). .
또한, 동물모델을 이용한 성장호르몬 분비촉진 실험 결과, 맥문동 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 an animal model, the extract was found to be a strong increase in growth hormone in vitro ( in vitro ) as well as in vivo (see Table 2 ).
또한, 본 발명은 맥문동 추출물을 유효성분으로 함유하는 성장호르몬 분비촉진용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for promoting growth hormone secretion containing Macmundong extract as an active ingredient.
본 발명의 성장호르몬 분비촉진용 약학적 조성물은 상기 맥문동 추출물을 유효 성분으로 함유한다. 상기 맥문동 추출물은 임상 투여 시에 경구 또는 비경구로 투여가 가능하며 일반적인 의약품 제제의 형태로 사용될 수 있다. 즉, 본 발명의 맥문동 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 맥문동 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 Macmundong as an active ingredient. The Macmundong 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 may 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.
맥문동 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 pulsed extract is 0.1 to 40 mg / kg, preferably 0.4 to 4 mg / kg, and may be administered 1-6 times a day.
본 발명의 맥문동 추출물을 마우스에 경구 투여, 복강 내 투여시 및 피하 주사시의 독성 실험을 수행한 결과, 복강 내 투여 및 피하 주사 독성 실험에 의한 50% 치사량(LD50)은 적어도 릴리오프(Liriope) 속의 맥문동 물 추출물 134.34 ±12.50 g/kg 이고 오피오포곤(Ophiopogon) 속의 소엽맥문동 물 추출물은 20.61 ±7.08 g/kg 이상인 안전한 물질로 판명되었다.As a result of conducting oral administration, intraperitoneal administration, and subcutaneous injection of the pulmonary sinus extract of the present invention to mice, 50% lethal dose (LD 50 ) by intraperitoneal administration and subcutaneous injection toxicity test was at least a Liliope. The pulmonary vegetation extract of 134.34 ± 12.50 g / kg and the leaflet vegetative extract of Ophiopogon were found to be safe substances of 20.61 ± 7.08 g / kg.
또한, 본 발명은 맥문동 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 맥문동 추출물을 첨가함으로써 일반 식품의 기능을 향상시킨 식품이며, 맥문동 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 improves the function of the general food by adding the medicinal extract to the general food, the medicinal 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 맥문동 추출물을 식품 첨가물로 사용할 경우, 상기 맥문동 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, 맥문동 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 맥문동 추출물을 함유한다.When using the medicinal extract of the present invention as a food additive, the medicinal extract may be added as it is or used 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 may 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 the wormwood extract within the toxic range measured when used in the pharmaceutical composition.
상기 식품의 종류에는 특별한 제한은 없다. 상기 맥문동 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, 맥문동 추출물을 함유하는 건강 식품으로는 맥문동을 주성분으로 만든 즙, 차, 젤리, 쥬스 등의 건강식품 및 기호품을 들 수 있으며, 점활성 소염, 진해, 거담, 지갈등을 목적으로 하는 민간요법제 등을 들 수 있다. There is no particular limitation on the kind of food. Examples of foods to which the extract may be 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 foods containing the extract of Megmun-dong include health foods and favorite products such as juice, tea, jelly, juice, etc., which are made mainly of Megmun-dong, and are used for the purpose of viscous anti-inflammatory, Jinhae, sputum, and jigal. Therapeutic agents etc. are 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> 맥문동 추출물의 제조 1Example 1 Preparation of Macmundong Extract 1
맥문동 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 맥문동 추출물을 제조하였다.50 g of dried powder 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 the extract of the present invention.
<실시예 2> 맥문동 추출물의 제조 2Example 2 Preparation of Macmundong Extract 2
맥문동 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 1>과 동일하게 본 발명의 맥문동 추출물을 제조하였다.0.1 g of dried powder powder was added to 1 ml of 1 N HCl aqueous solution and reacted at 100 ° C. for 2 hours. After hydrolysis for 2 hours and neutralized, the reaction solution was lyophilized to remove moisture, and thus, the extract of Macmundong 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.
맥문동 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 Macmundong 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.
맥문동 추출물 1 gMegmundong extract 1 g
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 맥문동 추출물을 유효성분 2% (중량/부피)로 함유하는 시럽은 다음과 같은 방법으로 제조한다. Syrup containing 2% (weight / volume) of the active ingredient of McMangdong extract of the present invention is prepared by the following method.
맥문동 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. Macmundong 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.
맥문동 추출물 2 gMegmundong Extract 2 g
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.
맥문동 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 Macmundong 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.
맥문동 추출물 250 g250 g of Macmundong 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 맥문동 추출물을 유효성분으로 함유하는 식품 또는 음료 조성물을 하기와 같이 제조하였다.The present inventors prepared the food or beverage composition containing the extract as the 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
맥문동 추출물 0.1 ∼ 0.5 ㎏Megmundong extract 0.1-0.5 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
맥문동 추출물 0.48 ∼ 1.28 ㎎Megmundong 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> 맥문동 추출물을 이용한 성장호르몬 분비촉진 활성실험Experimental Example 1 Growth Hormone Secretion Activity Test Using Macmundong Extract
<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 맥문동 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 실험 1Experimental Example 2 Growth Hormone-induced Experiment of Rat 1
6주령의 스프래그-다우리 랫트를 사용하여 맥문동 추출물을 1회 복강 투여한 후 유발된 혈중 성장호르몬의 농도를 측정하였다. 각 실험군당 수 마리씩의 랫트에 맥문동 추출물을 주사액에 용해하여 맥문동 4 mg/kg/ml의 용량으로 복강 주사한 후 마취 후 수 시간 동안 10분 간격으로 꼬리정맥에서 채혈하였다. 대조군은 주사액만 해당량을 주사한 후 동일시간 동안 채혈하였다. 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.Six-week-old Sprague-Dawley rats were administered intraperitoneally with Macmundong extract to determine the concentration of induced growth hormone. Several rats in each experimental group were dissolved in an injection solution of Macmundong extract in an intraperitoneal injection at a dose of 4mg / kg / ml, followed by blood collection from the tail vein at intervals of 10 minutes for several hours after anesthesia. In the control group, blood was injected for the same time after only the injection of the corresponding amount. 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.
그 결과, 맥문동 추출물을 투여한 군은 주사한 후 1시간 이내에 대조군에 비해 약 10-15배 정도의 성장호르몬 농도가 증가되는 것을 확인하였다. 이로써 맥문동 추출물은 시험관(in vitro) 및 생체내(in vivo)에서 대조군에 비해 성장호르몬을 강력하게 증가시키는 것을 입증하였다.As a result, it was confirmed that the group administered with the extract of Magmundong increased the growth hormone concentration about 10-15 times compared to the control within 1 hour after injection. This proved that Macmundong extract strongly increased growth hormone compared to the control in vitro and in vivo .
<실험예 3> 랫트의 성장호르몬 유발 실험 2Experimental Example 3 Induction of Growth Hormone in Rats 2
8주령의 스프래그-다우리 랫트를 펜토바비탈(pentobarbital) 50 mg/kg 농도로 마취시킨 후 맥문동 추출물을 건조약재 1 mg/kg 농도로 생리식염수에 용해시켜 랫트의 경정맥에 투여하였으며 대조군으로는 생리식염수를 투여하였다. 꼬리 경정맥으로부터 일정 시간간격으로 채혈한 후 상기 실험예 2와 동일하게 RIA 키트를 사용하여 분비된 성장호르몬을 측정하였다.Eight weeks-old Sprague-Dawley rats were anesthetized at a concentration of 50 mg / kg of pentobarbital, and the extracts of McMoon-dong were dissolved in physiological saline at a concentration of 1 mg / kg of dry medicine and administered to the jugular vein of rats. Physiological saline was administered. After the blood was collected from the tail jugular vein at a predetermined time interval, growth hormone secreted using the RIA kit was measured in the same manner as in Experimental Example 2.
상기 표 2에서 보는 바와 같이 동물을 이용하여 본 발명의 맥문동 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 60분 후 약 5배 정도의 증가를 보였으며 90분 이내에 맥문동 추출물의 성장호르몬 분비 촉진 능력이 측정되었다(도 1).As shown in Table 2 above, the medicinal extract of the present invention was administered to the jugular vein of the rat at a concentration of 1 mg / kg of dry medicinal herbs after the blood was collected from the tail vein at regular intervals to measure the growth hormone of the separated plasma. As a result, it was increased about 5 times after 60 minutes of drug administration compared with the control group, and the growth hormone secretion ability of the wormwood extract was measured within 90 minutes ( FIG. 1 ).
<실험예 4> 랫트에 대한 경구투여 급성 독성실험Experimental Example 4 Acute Toxicity in Rats
6주령의 특정병원체부재(specific pathogen-free, SPF) SD계 랫트를 사용하여 급성독성실험을 실시하였다. 군당 2 마리씩의 동물에 본 발명의 맥문동 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 0.5% methylcellulose solution, respectively, in the munmundong 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 맥문동 추출물은 모두 마우스에서 30 g 추출물/㎏까지 독성변화를 나타내지 않으며 경구 투여 최소치사량(LD50)은 추출물 134.34 ±12.50 g/kg 이상인 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 did not show a toxic change up to 30 g extract / kg in mice, and the minimum lethal dose (LD 50 ) of the oral administration was determined to be a safe substance having an extract of 134.34 ± 12.50 g / kg or more.
상기에서 살펴본 바와 같이, 본 발명의 맥문동 추출물은 매우 높은 성장호르몬 분비촉진 활성을 나타내고 이 추출물의 원료인 맥문동이 오래 동안 사용되어온 인체에 무해하고 흡수율이 좋은 천연약재이므로 성장호르몬과 관련된 각종 질환의 치료 및 예방에 유용하게 사용될 수 있다. As described above, the mammundong extract of the present invention exhibits a very high growth hormone secretagogue activity, and the raw material of this extract is harmless to humans and has good absorption rate for a long time. And can be usefully used for prevention.
도 1은 본 발명의 맥문동 추출물을 랫트의 경정맥에 투여한 후 꼬리 정맥으로부터 일정 시간 간격으로 성장호르몬을 측정한 것을 그래프로 나타낸 것이다. 1 is a graph showing the growth hormone was measured at regular time intervals from the tail vein after administering the pulmonary sinus extract of the present invention to the jugular vein of the rat.
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