KR102625308B1 - Composition for preventing or treating metabolic disorders related to hyperuricemia or hyperuricemia comprising hydrangenol or phyllodulcin - Google Patents
Composition for preventing or treating metabolic disorders related to hyperuricemia or hyperuricemia comprising hydrangenol or phyllodulcin Download PDFInfo
- Publication number
- KR102625308B1 KR102625308B1 KR1020210072974A KR20210072974A KR102625308B1 KR 102625308 B1 KR102625308 B1 KR 102625308B1 KR 1020210072974 A KR1020210072974 A KR 1020210072974A KR 20210072974 A KR20210072974 A KR 20210072974A KR 102625308 B1 KR102625308 B1 KR 102625308B1
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- KR
- South Korea
- Prior art keywords
- hyperuricemia
- weight
- gouty
- hydrangenol
- phyllodulcin
- Prior art date
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Abstract
일 양상의 조성물은 고요산혈증 또는 고요산혈증 관련 대사 장애 매개 인자인 잔틴산화효소(Xanthine Oxidase)의 활성을 저해하여 요산의 생성을 억제하고, 요산 결정으로 유발되는 염증을 완화시킴으로써, 고요산혈증 또는 고요산혈증 관련 대사 장애를 치료하는 효과가 있다.The composition of one aspect inhibits the production of uric acid by inhibiting the activity of xanthine oxidase, a mediator of hyperuricemia or hyperuricemia-related metabolic disorders, and relieves inflammation caused by uric acid crystals. It is effective in treating related metabolic disorders.
Description
본 발명은 고요산혈증 또는 고요산혈증 관련 대사 장애의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating hyperuricemia or hyperuricemia-related metabolic disorders.
요산은 퓨린이라는 핵산 성분이 분해되면서 생기는 노폐물로, 정상인은 소변과 대변으로 대부분 배설되는데, 요산이 과다 생성되거나 배출이 원활하지 않아 혈액, 체액 또는 관절액에 과다하게 존재하는 것을 고요산혈증이라고 한다.Uric acid is a waste product produced when a nucleic acid component called purine is decomposed. In normal people, it is mostly excreted through urine and feces. However, hyperuricemia occurs when uric acid is excessively produced or excreted excessively, resulting in excessive presence in the blood, body fluids, or joint fluid.
고요산혈증은 남성에서 6.8 내지 7.0mg/dL 초과 또는 여성에서 6mg/dL 초과의 혈중 요산 값을 가지는 경우로 정의된다. 고요산혈증 및 고요산혈증 관련 대사 장애들(예를 들면, 통풍)은 미국에서 3백만 명 내지 5백만 명에게서 발생하고, 1990년과 2010년 사이에 통풍의 발생률이 대략 2배로 증가하였으며, 국내 통풍 환자 수는 연평균 14% 정도씩 증가하는 추세를 보이고 있다.Hyperuricemia is defined as having a blood uric acid level greater than 6.8 to 7.0 mg/dL in men or greater than 6 mg/dL in women. Hyperuricemia and hyperuricemia-related metabolic disorders (e.g., gout) occur in 3 to 5 million people in the United States, and the incidence of gout approximately doubled between 1990 and 2010. The number shows a trend of increasing by an average of 14% per year.
고요산혈증 관련 대사 장애에는 통풍뿐만 아니라, 요산 결정, 관절 내 요산염 결정의 침착, 신질부 내 요산염 결정의 침착으로 인한 급성, 단일 관절성, 염증성 관절염의 통증 발작, 요로 결석증, 신결석증 및 통풍성 신병증이 포함된다. 고요산혈증 관련 대사 장애 중에서 통풍은 혈액 내에 요산의 농도가 높아지면서 요산염 결정이 관절의 연골, 힘줄, 주위 조직에 침착되는 질병이다. Hyperuricemia-related metabolic disorders include not only gout, but also uric acid crystals, deposition of urate crystals in joints, painful attacks of acute, monoarticular, inflammatory arthritis due to deposition of urate crystals in renal parts, urolithiasis, nephrolithiasis, and gout. Includes nephropathy. Among metabolic disorders related to hyperuricemia, gout is a disease in which urate crystals are deposited in joint cartilage, tendons, and surrounding tissues as the concentration of uric acid in the blood increases.
통풍의 치료 방법으로는, 혈중 요산 농도를 포화상태 이하로 장기간 유지하면 급성 통풍성 관절염의 예방뿐 아니라 이미 생긴 통풍 결절의 크기를 줄일 수 있다는 것을 이용하여 잔틴 산화효소(xanthine oxidase) 저해제와 요산배출촉진제(uricosuric agent)를 이용한 혈중의 요산농도를 낮추는 치료를 수행하는 것이 일반적이다. 그러나, 합성 화학품을 기반으로 한 공지된 통풍 치료 약물은 부작용의 위험도가 큰 문제점이 있었다.As a treatment method for gout, xanthine oxidase inhibitors and uric acid excretion promoters are used, taking advantage of the fact that maintaining blood uric acid concentration below the saturation level for a long period of time can not only prevent acute gouty arthritis but also reduce the size of gouty nodules that have already formed. It is common to perform treatment to lower the uric acid concentration in the blood using a uricosuric agent. However, known gout treatment drugs based on synthetic chemicals have the problem of high risk of side effects.
특히, 예방 치료는 병이 진정 상태로 일정기간 유지된 후에 사용할 필요가 있으며, 적절한 시기에 사용하지 않는 통풍이 더 심하게 재발하는 문제점 또한 존재하여 사용이 쉽지 않았다. 따라서, 부작용의 위험이 적고, 통풍을 미리 예방하는 데에 효과가 높은 조성물의 개발이 시급한 실정이다.In particular, preventive treatment needs to be used after the disease has been maintained in a sedated state for a certain period of time, and there is also the problem of more severe recurrence of gout if not used at the appropriate time, making it difficult to use. Therefore, there is an urgent need to develop a composition that has a low risk of side effects and is highly effective in preventing gout.
식물유래 소재는 안전성 측면에서 우수하여 오랫동안 이용되었으며, 특히 국내의 경우 민간에서 이용되거나 혹은 한방에서 이용되는 식물 및 생약성분을 주로 한 기능성 소재 개발이 활발히 이루어지고 있다.Plant-derived materials have been used for a long time because they are excellent in terms of safety. In particular, in Korea, the development of functional materials mainly made of plants and herbal ingredients used in the private sector or in oriental medicine is actively being developed.
하이드란제놀(Hydrangenol)은 수국속(Hydrangea)에서 발견되는 대표적인 성분으로서(일본공개특허 JP0029934), 분자량은 256.25 g/mol이며 IUPAC명은 8-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydroisochromen-1-one이다. 또한, 이것의 유도체로는(-)-hydrangenol 4'-O-glucoside, (+)-hydrangenol 4'-O-glucoside가 있다. 이것의 기능성으로는 피부미백(일본공개특허 JP-0007546), 항염효과(Kim, H.J, et al., Hydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-mediated HO-1 pathway, International immunopharmacology v.35, pp. 61 - 69, 2016, 1567-5769)가 있는 것으로 보고된 바 있다.Hydrangenol is a representative ingredient found in Hydrangea (Japanese Patent Publication JP0029934). Its molecular weight is 256.25 g/mol and its IUPAC name is 8-hydroxy-3-(4-hydroxyphenyl)-3,4- It is dihydroisochromen-1-one. Additionally, its derivatives include (-)-hydrangenol 4'-O-glucoside and (+)-hydrangenol 4'-O-glucoside. Its functionality includes skin whitening (Japanese published patent JP-0007546), anti-inflammatory effect (Kim, HJ, et al., Hydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2 -mediated HO-1 pathway, International immunopharmacology v.35, pp. 61 - 69, 2016, 1567-5769).
필로둘신(Phyllodulcin; C16H14O5;(R)-3,4-dihydroxy-3-(4-methoxy-3-hydroxyphenyl) isocoumarine)은 수국속에서 발견되는 성분으로서 수국차 특유의 천연 비당성 단맛은 이 성분에 의해 발현된다. 필로둘신은 수국잎에 배당체 형태로 존재하지만 내재하는 베타 클루코시다아제(β-glucosidase)에 의해 필로둘신으로 생전환되어, 약 350~800배의 상대당도를 나타낸다고 알려져 있다(Chem Pharm Bull 1978, 26, 2321-2327; Arig Biol Chem 1977, 41, 719-720; J Nat Prod 2004, 67, 1604-1607). 항알레르기 및 항궤양성(Nat Med 1994, 114, 401-413), 항비만(Nutrients 2017, 9(10)), 당뇨병 예방 및 개선(한국공개특허 10-2016-0095576) 등의 효과가 알려져 있다. Phyllodulcin (C 16 H 14 O 5 ;(R)-3,4-dihydroxy-3-(4-methoxy-3-hydroxyphenyl) isocoumarine) is a component found in hydrangea and is a natural non-sugar substance unique to hydrangea tea. Sweetness is expressed by this ingredient. Phylodulcine exists in the form of glycosides in hydrangea leaves, but is converted to phyllodulcine by inherent beta-glucosidase, and is known to have a relative sugar content of about 350 to 800 times (Chem Pharm Bull 1978, 26, 2321-2327; Arig Biol Chem 1977, 41, 719-720; J Nat Prod 2004, 67, 1604-1607). It is known to have anti-allergy and anti-ulcer properties (Nat Med 1994, 114, 401-413), anti-obesity (Nutrients 2017, 9(10)), and diabetes prevention and improvement (Korea Patent Publication No. 10-2016-0095576). .
그러나, 상기 식물의 통풍 질환의 예방 또는 개선, 치료에 대한 용도는 알려지지 않았으며, 그에 대한 기전 연구도 이루어지지 않은 실정이다.However, the use of the plant for preventing, improving, or treating gout disease is unknown, and no mechanistic studies have been conducted on it.
이에, 본 발명자들은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 포함하는 조성물의 경우, 잔틴산화효소의 활성을 저해하여 요산의 생성을 억제하고, 요산 결정으로 유발되는 염증을 완화시킴으로써 통풍 질환의 개선효과를 나타낼 수 있음을 확인하여 위와 같은 문제점을 극복하였다.Accordingly, the present inventors have found that a composition containing Hydrangenol, Phyllodulcin or an acceptable salt thereof inhibits the activity of xanthine oxidase, thereby inhibiting the production of uric acid and preventing the formation of uric acid caused by uric acid crystals. The above problems were overcome by confirming that gout disease can be improved by alleviating inflammation.
일 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 예방용 건강기능식품 조성물을 제공한다.One aspect provides a health functional food composition for improving or preventing hyperuricemia or hyperuricemia-related metabolic disorders containing Hydrangenol, Phyllodulcin or an acceptable salt thereof as an active ingredient.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for improving or treating hyperuricemia or hyperuricemia-related metabolic disorders containing Hydrangenol, Phyllodulcin or an acceptable salt thereof as an active ingredient.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 잔틴산화효소(Xanthine oxidase) 저해용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for inhibiting xanthine oxidase containing Hydrangenol, Phyllodulcin, or an acceptable salt thereof as an active ingredient.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 예방용 의약외품 조성물을 제공한다.Another aspect provides a quasi-drug composition for improving or preventing hyperuricemia or hyperuricemia-related metabolic disorders containing Hydrangenol, Phyllodulcin or an acceptable salt thereof as an active ingredient.
일 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 예방용 건강기능식품 조성물을 제공한다.One aspect provides a health functional food composition for improving or preventing hyperuricemia or hyperuricemia-related metabolic disorders containing Hydrangenol, Phyllodulcin or an acceptable salt thereof as an active ingredient.
본 명세서에서 용어 "하이드란제놀(Hydrangenol)"은 이소쿠마린(isocoumarin) 관련 페놀계 화학물인 다이하이드로아이소쿠마린(Dihydroisocoumarin)의 일종으로서, 8-Hydroxy-3-(4-hydroxyphenyl)-1H-2-benzopyran-1-one라고도 명명되는 것일 수 있다.As used herein, the term "Hydrangenol" refers to a type of dihydroisocoumarin, a phenol-based chemical related to isocoumarin, 8-Hydroxy-3-(4-hydroxyphenyl)-1H-2- It may also be named benzopyran-1-one.
상기 하이드란제놀은 하기 화학식 1의 구조를 가지거나, 화학식 1로 표시되는 것일 수 있다.The hydrangenol may have the structure of Formula 1 below or may be represented by Formula 1.
[화학식 1][Formula 1]
본 명세서에서 용어 "필로둘신(Phyllodulcin)"은 이소쿠마린(isocoumarin) 관련 페놀계 화학물인 다이하이드로아이소쿠마린(Dihydroisocoumarin)의 일종으로서, (3R)-8-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-3,4-dihydroisochromen-1-one라고도 명명된다.As used herein, the term "Phyllodulcin" refers to a type of dihydroisocoumarin, a phenolic chemical related to isocoumarin, (3R)-8-hydroxy-3-(3-hydroxy-4- It is also called methoxyphenyl)-3,4-dihydroisochromen-1-one.
상기 필로둘신은 하기 화학식 2의 구조를 가지거나, 화학식 2로 표시되는 것일 수 있다.The phyllodulcine may have the structure of Formula 2 below or may be represented by Formula 2.
[화학식 2] [Formula 2]
상기 조성물은 하이드란제놀(Hydrangenol)의 유도체 또는 필로둘신(Phyllodulcin)의 유도체를 포함하는 것일 수 있다.The composition may include a derivative of Hydrangenol or a derivative of Phyllodulcin.
본 명세서에서 용어, "유도체(derivative)”는, 화합물의 일부를 화학적으로 변화시켜서 얻어지는 유사한 화합물을 의미한다. 상기 유도체는 화합물 중의 수소원자 또는 특정 원자단이 다른 원자 또는 원자단에 의하여 치환된 화합물일 수 있다.As used herein, the term "derivative" refers to a similar compound obtained by chemically changing part of a compound. The derivative may be a compound in which a hydrogen atom or a specific atomic group in the compound is replaced by another atom or group. there is.
일 구체예에 있어서, 상기 하이드란제놀 또는 필로둘신은 수국속(Hydrangea) 추출물로부터 분리된 것일 수 있다. 상기 수국속 추출물은 산수국(Hydrangea macrophylla 또는 Hydrangea serrata) 추출물일 수 있다.In one embodiment, the hydrangenol or phyllodulcine may be isolated from Hydrangea extract. The Hydrangea genus extract may be an extract of Hydrangea macrophylla or Hydrangea serrata.
일 구체예에 있어서, 상기 수국속 추출물은 폴리페놀 또는 플라보노이드를 포함하고 있는 것일 수 있다.In one embodiment, the Hydrangea extract may contain polyphenols or flavonoids.
일 구체예에서 폴리페놀은 항염, 항산화 효과를 가지며, 폴리페놀 섭취는 요산 수치 감소 효과를 나타낼 수 있다. 또한, 일 구체예에서 플라보노이드는 요산의 생성을 억제해 요산요에 의한 염증을 완화해주는 효과를 나타낼 수 있다.In one embodiment, polyphenols have anti-inflammatory and antioxidant effects, and polyphenol intake can have the effect of reducing uric acid levels. Additionally, in one embodiment, flavonoids can inhibit the production of uric acid and thereby have the effect of alleviating inflammation caused by uric acid.
일 구체예에 있어서, 상기 수국속 추출물, 이로부터 분리된 하이드란제놀 또는 필로둘신은 세포의 항산화능을 증가시키거나, 초과 산화물분균등화효소(SOD)의 활성을 높이거나, 잔틴산화효소의 활성을 저해하거나 또는 NO를 감소시키는 것일 수 있다.In one embodiment, the Hydrangea extract and hydrangenol or phyllodulcine isolated therefrom increase the antioxidant capacity of cells, increase the activity of superoxide dehydrogenase (SOD), or increase the activity of xanthine oxidase. It may inhibit or reduce NO.
일 구체예에 있어서, 상기 수국속 추출물, 이로부터 분리된 하이드란제놀 또는 필로둘신 중 하나를 유효성분으로 포함하는 조성물은 IL-1β 발현 수치 또는 TNF-α 발현 수치를 감소시킬 수 있다.In one embodiment, a composition containing the Hydrangea extract or one of hydrangenol or phyllodulcine isolated therefrom as an active ingredient may reduce the expression level of IL-1β or TNF-α.
일 구체예에 있어서, 상기 산수국의 추출물은 산수국의 전초, 뿌리, 줄기, 가지, 잎, 종자 및 열매로 이루어진 군으로부터 선택된 하나 이상의 것에서 추출한 것일 수 있다.In one embodiment, the extract of Wild Hydrangea may be extracted from one or more selected from the group consisting of whole plants, roots, stems, branches, leaves, seeds, and fruits of Wild Hydrangea.
일 구체예에 있어서, 상기 추출물은 물, 알콜, 예를 들면, C1-C6 알콜, 예를 들면, C1-C4 알콜 또는 이들의 혼합물을 용매로 하여 추출된 것일 수 있다. 상기 C1-C6 알콜은 메탄올, 에탄올, 프로판올, 이소프로판올, 1,3-프로판디올, 부탄올, 펜탄올, 헥산올 등일 수 있다.In one embodiment, the extract may be extracted using water, alcohol, for example, C1-C6 alcohol, for example, C1-C4 alcohol, or a mixture thereof as a solvent. The C1-C6 alcohol may be methanol, ethanol, propanol, isopropanol, 1,3-propanediol, butanol, pentanol, hexanol, etc.
일 구체예에 있어서, 상기 추출은 각 추출물에 대하여 상기 추출 용매를 3 내지 10(부피 또는 중량)배, 예를 들면, 3 내지 7(부피/중량)배, 3 내지 5(부피/중량)배, 5 내지 10(부피/중량)배, 또는 4 내지 10(부피/중량)배 첨가하는 것을 포함할 수 있다.In one embodiment, the extraction is performed by using 3 to 10 (volume or weight) times the extraction solvent for each extract, for example, 3 to 7 (volume/weight) times, 3 to 5 (volume/weight) times. , may include adding 5 to 10 (volume/weight) times, or 4 to 10 (volume/weight) times.
일 구체예에 있어서, 상기 용매는 물과 알콜의 혼합물 즉 알콜 수용액일 수 있으며, 에탄올 수용액일 수 있다. 상기 알콜 수용액의 알콜 농도는 1 내지 99.5 (v/v)%, 10 내지 99.5 (v/v)%, 1 내지 70(v/v)%, 1 내지 40 (v/v)%, 5 내지 25 (v/v)%, 7 내지 20 (v/v)%, 5 내지 25 (v/v)%, 또는 10 내지 20(v/v)%일 수 있다. In one embodiment, the solvent may be a mixture of water and alcohol, that is, an aqueous alcohol solution, or an aqueous ethanol solution. The alcohol concentration of the alcohol aqueous solution is 1 to 99.5 (v/v)%, 10 to 99.5 (v/v)%, 1 to 70 (v/v)%, 1 to 40 (v/v)%, 5 to 25%. (v/v)%, 7 to 20 (v/v)%, 5 to 25 (v/v)%, or 10 to 20 (v/v)%.
일 구체예에 있어서, 상기 수국속 추출물은 조성물 총 중량 대비 0.0001 중량% 내지 99.0 중량%, 예를 들면, 0.01 중량% 내지 60 중량%, 0.01 중량% 내지 40 중량%, 0.01 중량% 내지 30 중량%, 0.01 중량% 내지 20 중량%, 0.01 중량% 내지 10 중량%, 0.01 중량% 내지 5 중량%, 0.05 중량% 내지 60 중량%, 0.05 중량% 내지 40 중량%, 0.05 중량% 내지 30 중량%, 0.05 중량% 내지 20 중량%, 0.05 중량% 내지 10 중량%, 0.05 중량% 내지 5 중량%, 0.1 중량% 내지 60 중량%, 0.1 중량% 내지 40 중량%, 0.1 중량% 내지 30 중량%, 0.1 중량% 내지 20 중량%, 0.1 중량% 내지 10 중량%, 또는 0.1 중량% 내지 5 중량% 포함되는 것일 수 있다. 또한, 상기 수국속 추출물은 조성물 총 중량 대비 5 내지 20 중량%, 5 내지 18 중량%, 6 내지 15 중량%, 8 내지 15중량%, 7 내지 10 중량% 포함되는 것일 수 있다.In one embodiment, the Hydrangea extract is 0.0001% to 99.0% by weight, for example, 0.01% to 60% by weight, 0.01% to 40% by weight, 0.01% to 30% by weight, based on the total weight of the composition. , 0.01% to 20% by weight, 0.01% to 10% by weight, 0.01% to 5% by weight, 0.05% to 60% by weight, 0.05% to 40% by weight, 0.05% to 30% by weight, 0.05% by weight. Weight % to 20 weight %, 0.05 weight % to 10 weight %, 0.05 weight % to 5 weight %, 0.1 weight % to 60 weight %, 0.1 weight % to 40 weight %, 0.1 weight % to 30 weight %, 0.1 weight % It may contain from 20 wt%, 0.1 wt% to 10 wt%, or 0.1 wt% to 5 wt%. In addition, the Hydrangea extract may be included in an amount of 5 to 20% by weight, 5 to 18% by weight, 6 to 15% by weight, 8 to 15% by weight, and 7 to 10% by weight based on the total weight of the composition.
일 구체예에 있어서, 상기 수국속 추출물로부터 분리된 하이드란제놀은 조성물 총 중량 대비 0.0001 중량% 내지 99.0 중량%, 예를 들면, 0.01 중량% 내지 60 중량%, 0.01 중량% 내지 40 중량%, 0.01 중량% 내지 30 중량%, 0.01 중량% 내지 20 중량%, 0.01 중량% 내지 10 중량%, 0.01 중량% 내지 5 중량%, 0.05 중량% 내지 60 중량%, 0.05 중량% 내지 40 중량%, 0.05 중량% 내지 30 중량%, 0.05 중량% 내지 20 중량%, 0.05 중량% 내지 10 중량%, 0.05 중량% 내지 5 중량%, 0.1 중량% 내지 60 중량%, 0.1 중량% 내지 40 중량%, 0.1 중량% 내지 30 중량%, 0.1 중량% 내지 20 중량%, 0.1 중량% 내지 10 중량%, 또는 0.1 중량% 내지 5 중량% 포함되는 것일 수 있다. 또한, 상기 수국속 추출물로부터 분리된 하이드란제놀은 조성물 총 중량 대비 5 내지 20 중량%, 5 내지 18 중량%, 6 내지 15 중량%, 8 내지 15중량%, 7 내지 10 중량% 포함되는 것일 수 있다.In one embodiment, the hydrangenol isolated from the Hydrangea extract is 0.0001% by weight to 99.0% by weight, for example, 0.01% by weight to 60% by weight, 0.01% by weight to 40% by weight, 0.01% by weight, based on the total weight of the composition. Weight % to 30 weight %, 0.01 weight % to 20 weight %, 0.01 weight % to 10 weight %, 0.01 weight % to 5 weight %, 0.05 weight % to 60 weight %, 0.05 weight % to 40 weight %, 0.05 weight % to 30% by weight, 0.05% to 20% by weight, 0.05% to 10% by weight, 0.05% to 5% by weight, 0.1% to 60% by weight, 0.1% to 40% by weight, 0.1% to 30% by weight. It may be included in weight%, 0.1% by weight to 20% by weight, 0.1% by weight to 10% by weight, or 0.1% by weight to 5% by weight. In addition, hydrangenol isolated from the Hydrangea extract may be included in an amount of 5 to 20% by weight, 5 to 18% by weight, 6 to 15% by weight, 8 to 15% by weight, and 7 to 10% by weight based on the total weight of the composition. there is.
일 구체예에 있어서, 상기 수국속 추출물로부터 분리된 필로둘신은 조성물 총 중량 대비 0.0001 중량% 내지 99.0 중량%, 예를 들면, 0.01 중량% 내지 60 중량%, 0.01 중량% 내지 40 중량%, 0.01 중량% 내지 30 중량%, 0.01 중량% 내지 20 중량%, 0.01 중량% 내지 10 중량%, 0.01 중량% 내지 5 중량%, 0.05 중량% 내지 60 중량%, 0.05 중량% 내지 40 중량%, 0.05 중량% 내지 30 중량%, 0.05 중량% 내지 20 중량%, 0.05 중량% 내지 10 중량%, 0.05 중량% 내지 5 중량%, 0.1 중량% 내지 60 중량%, 0.1 중량% 내지 40 중량%, 0.1 중량% 내지 30 중량%, 0.1 중량% 내지 20 중량%, 0.1 중량% 내지 10 중량%, 또는 0.1 중량% 내지 5 중량% 포함되는 것일 수 있다. 또한, 상기 수국속 추출물로부터 분리된 필로둘신은 조성물 총 중량 대비 5 내지 20 중량%, 5 내지 18 중량%, 6 내지 15 중량%, 8 내지 15중량%, 7 내지 10 중량% 포함되는 것일 수 있다.In one embodiment, the phyllodulcine isolated from the Hydrangea extract is 0.0001% to 99.0% by weight, for example, 0.01% to 60% by weight, 0.01% to 40% by weight, 0.01% by weight, based on the total weight of the composition. % to 30% by weight, 0.01% to 20% by weight, 0.01% to 10% by weight, 0.01% to 5% by weight, 0.05% to 60% by weight, 0.05% to 40% by weight, 0.05% to 0.05% by weight. 30% by weight, 0.05% to 20% by weight, 0.05% to 10% by weight, 0.05% to 5% by weight, 0.1% to 60% by weight, 0.1% to 40% by weight, 0.1% to 30% by weight %, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, or 0.1 wt% to 5 wt%. In addition, phyllodulcine isolated from the Hydrangea genus extract may be included in an amount of 5 to 20% by weight, 5 to 18% by weight, 6 to 15% by weight, 8 to 15% by weight, and 7 to 10% by weight based on the total weight of the composition. .
본 발명의 수국속 추출물을 얻기 위한 추출 방법은 본 발명이 속하는 기술분야의 통상적으로 사용되는 공지된 추출 방법에 따라 제조될 수 있다. 구체적으로 냉침법, 가열 추출법, 초음파 추출법, 여과법, 가압추출법, 환류추출법, 초임계 추출법, 전기적 추출법 등 통상적으로 사용되는 추출법을 사용할 수 있으며, 통상의 추출기기, 초음파분쇄 추출기 또는 분획기를 이용할 수 있다.The extraction method for obtaining the Hydrangea extract of the present invention can be prepared according to a known extraction method commonly used in the technical field to which the present invention pertains. Specifically, commonly used extraction methods such as cold immersion method, heat extraction method, ultrasonic extraction method, filtration method, pressure extraction method, reflux extraction method, supercritical extraction method, and electric extraction method can be used. Ordinary extraction equipment, ultrasonic grinding extractor or fractionator can be used. .
또한, 필요한 경우 상기 추출 후, 당업계에 공지된 여과 및/또는 농축 및/또는 동결건조 방법을 추가적으로 사용할 수 있다. 본 발명에서 사용된 추출물의 건조물 또는 농축물은 상기와 같이 공지된 방법으로 건조 또는 농축된 것을 의미한다.Additionally, if necessary, after the extraction, filtration and/or concentration and/or freeze-drying methods known in the art may be additionally used. The dried product or concentrate of the extract used in the present invention means dried or concentrated by a known method as described above.
본 명세서에서 용어 "유효성분" 은 약리작용에 의하여 그 의약품의 효능 또는 효과를 직접 또는 간접적으로 발현한다고 기대되는 물질 또는 물질 군을 의미한다. 용어 "유효량"은 질환, 장애 또는 병태, 또는 그의 하나 이상의 증상의 경감, 진행 억제 또는 예방에 충분한 본원에서 제공되는 발명을 실시하는 과정에서 이용되는 조성물의 임의의 양을 의미한다.As used herein, the term “active ingredient” refers to a substance or group of substances expected to directly or indirectly express the efficacy or effect of the drug through pharmacological action. The term “effective amount” means any amount of a composition used in practicing the invention provided herein that is sufficient to alleviate, inhibit the progression of, or prevent a disease, disorder, or condition, or one or more symptoms thereof.
본 명세서에서 용어 "고요산혈증"은 남성에서 6.5 내지 7.5mg/dL 초과 또는 여성에서 6mg/dL 초과의 혈중 요산 값을 갖는 질환을 의미한다. 상기 고요산혈증은 고혈압, 고지혈증, 혈당증가, 복부 비만 등의 임상양상을 수반할 수 있다. 또한, 상기 고요산혈증은 무증상 고요산혈증 또는 고요산혈증일 수 있다. As used herein, the term “hyperuricemia” refers to a disease having a blood uric acid value of greater than 6.5 to 7.5 mg/dL in men or greater than 6 mg/dL in women. The hyperuricemia may be accompanied by clinical features such as high blood pressure, hyperlipidemia, increased blood sugar, and abdominal obesity. Additionally, the hyperuricemia may be asymptomatic hyperuricemia or hyperuricemia.
본 명세서에서 용어 "고요산혈증 관련 대사 장애"는 혈액 내의 요산의 축척으로 인해 유발될 수 있는 질환을 총칭한다.As used herein, the term “hyperuricemia-related metabolic disorder” refers collectively to diseases that can be caused by the accumulation of uric acid in the blood.
일 구체예에 있어서, 상기 고요산혈증 관련 대사 장애는 급성 또는 만성통풍, 간헐기 통풍, 통풍성 발적, 통풍성 관절염, 급성 통풍성 관절염, 만성 결절성 통풍, 통풍성 신결석증, 신석증 및 통풍성 신병증으로 이루어진 군으로부터 선택된 하나 이상의 것일 수 있다.In one embodiment, the hyperuricemia-related metabolic disorder is from the group consisting of acute or chronic gout, intermittent gout, gout flares, gouty arthritis, acute gouty arthritis, chronic nodular gout, gouty nephrolithiasis, nephrolithiasis, and gouty nephropathy. There may be more than one selected.
본 명세서에서 용어 "무증상 고요산혈증"이란, 혈청 요산의 농도는 증가되어 있지만, 관절염 증상, 통풍결절, 요산 콩팥돌증 등의 증상은 아직 나타나지 않은 상태를 의미할 수 있다.As used herein, the term "asymptomatic hyperuricemia" may mean a state in which the concentration of serum uric acid is increased, but symptoms such as arthritis symptoms, gouty nodules, and uric acid nephrolithiasis have not yet appeared.
본 명세서에서 용어 "통풍"은 잔틴(Xanthine)이 잔틴 산화효소(Xanthine Oxidase)에 의해 산화됨으로써 생성되는 요산의 농도가 혈액 내에서 높아짐으로써, 요산염 결정이 관절의 연골, 힘줄, 주위 조직에 침착되어 염증 또는 통증이 수반되는 질병을 의미한다. 또한, 통풍은 관절의 염증, 재발성 발작, 관절의 변형과 불구, 또는 신장질환을 수반하며, 고혈압, 고지혈증, 혈당증가, 복부 비만 등의 임상양상을 가질 수 있다. 상기 통풍은 요산혈증, 급성 통풍성 관절염, 간헐기 통풍, 만성 결절성 통풍 등의 단계를 거쳐 나타날 수 있다. 또한, 상기 통풍은 단관절염, 소수관절염 또는 다관절염 형태일 수 있다.As used herein, the term "gout" refers to an increase in the concentration of uric acid in the blood, which is produced when xanthine is oxidized by xanthine oxidase, causing urate crystals to deposit in the cartilage, tendons, and surrounding tissues of the joint It refers to a disease that is accompanied by inflammation or pain. In addition, gout is accompanied by joint inflammation, recurrent attacks, joint deformation and disability, or kidney disease, and may have clinical manifestations such as high blood pressure, hyperlipidemia, increased blood sugar, and abdominal obesity. The gout may appear through stages such as uricemia, acute gouty arthritis, intermittent gout, and chronic nodular gout. Additionally, the gout may be in the form of monoarthritis, oligoarthritis, or polyarthritis.
본 명세서에서 용어 "통풍성 발적"은 통풍에 의한 염증 등으로 붉어지는 증상을 의미할 수 있다.As used herein, the term “gout-related redness” may refer to symptoms of redness due to inflammation caused by gout.
본 명세서에서 용어 "급성 통풍성 관절염"은 고요산혈증이 지난 후, 통풍 발작이 나타나거나 콩팥돌증이 발생하는 질환일 수 있다. 상기 통풍성 관절염은 관절염의 급성 발작, 심한 고통, 점차 여러 관절을 침범하는 특징, 고열과 같은 특징을 수반할 수 있다. 용어"간헐기 통풍"은 통풍 발작 사이의 증상이 없는 기간을 의미할 수 있으며, 간헐기 통풍은 첫 번째 발작 이후에 6개월에서 2년 사이의 간헐기를 갖는 형태의 통풍으로, 점차 빈도가 증가하고, 여러 관절을 침범하는 특징이 있다. 용어"만성 결절성 통증"은 통풍 발작이 일어나지 않은 간헐기 이후에 나타나는 통풍으로, 일반 관절염과 유사한 증상을 가지고 있고, 침범부위 관절에 점진적 뻣뻣함과 지속적인 통증이 발생하는 질환일 수 있다.As used herein, the term “acute gouty arthritis” may be a disease in which a gout attack occurs or nephrolithiasis occurs after hyperuricemia has passed. The gouty arthritis may be accompanied by characteristics such as acute attacks of arthritis, severe pain, gradual involvement of multiple joints, and high fever. The term "intermittent gout" can refer to the symptom-free period between gout attacks. Intermittent gout is a form of gout that has intermittent periods of six months to two years after the first attack, gradually increasing in frequency. , has the characteristic of involving multiple joints. The term "chronic nodular pain" refers to gout that appears after an intermittent period in which gout attacks do not occur. It has symptoms similar to general arthritis and may be a disease in which progressive stiffness and persistent pain occurs in the affected joint.
본 명세서에서 용어 "잔틴산화효소(Xanthine oxidase) 저해"는 체내에서 구아닌(guanine)은 직접 잔틴(xanthine)으로 대사되는 데에 기여하는 잔틴산화효소의 활성을 저해함으로서, 결과적으로 요산의 생성을 저해하는 것을 의미한다.As used herein, the term “xanthine oxidase inhibition” refers to inhibiting the activity of xanthine oxidase, which contributes to the direct metabolism of guanine into xanthine in the body, thereby inhibiting the production of uric acid. It means to do.
일 구체예에 있어서, 상기 조성물은 요산 생성을 억제함으로서, 혈중 요산 농도의 증가를 방지하여 고요산혈증 또는 고요산혈증 관련 대사 장애를 효과적으로 치료할 수 있다.In one embodiment, the composition can effectively treat hyperuricemia or hyperuricemia-related metabolic disorders by inhibiting uric acid production and preventing an increase in uric acid concentration in the blood.
본 명세서에서 용어 "항산화능의 증가" 체내의 DPPH 라디칼 소거능 또는 전자공여능을 증가시키는 것을 의미한다. 구체적으로, 상기 조성물은 잔틴 산화효소가 잔틴을 요산으로 전환시킬 때 생성되는 슈퍼옥사이드 라디칼(superoxide radical) 등을 제거하여 항산화능, 라디칼 소거능 또는 전자공여능을 증가시키는 것일 수 있다.As used herein, the term “increasing antioxidant capacity” refers to increasing the DPPH radical scavenging ability or electron donating ability in the body. Specifically, the composition may increase antioxidant ability, radical scavenging ability, or electron donating ability by removing superoxide radicals generated when xanthine oxidase converts xanthine into uric acid.
일 구체예에 있어서, 상기 조성물은 항산화능을 증가시킴으로써, 통풍으로 인한 염증을 예방 또는 치료하는 것일 수 있다.In one embodiment, the composition may prevent or treat inflammation caused by gout by increasing antioxidant activity.
일 구체예에 있어서, 상기 조성물은 IL-1β 발현을 감소시킴으로써, 통풍으로 인한 염증을 예방 또는 치료하는 것일 수 있다.In one embodiment, the composition may prevent or treat inflammation caused by gout by reducing IL-1β expression.
일 구체예에 있어서, 상기 조성물은 TNF-α 발현을 감소시킴으로써, 통풍으로 인한 염증을 예방 또는 치료하는 것일 수 있다.In one embodiment, the composition may prevent or treat inflammation caused by gout by reducing TNF-α expression.
상기 "건강기능식품"은 건강보조의 목적으로 특정성분을 원료로 하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말한다.The above-mentioned “health functional food” refers to a food manufactured or processed using specific ingredients as raw materials or specific ingredients contained in food ingredients by methods such as extraction, concentration, purification, mixing, etc. for the purpose of health supplementation. It refers to food designed and processed to fully exert bioregulatory functions on the living body, such as defense, regulation of biological rhythm, prevention and recovery of disease, etc.
상기 건강기능식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 건강기능식품의 제조에 통상적으로 사용되는 적절한 담체를 포함할 수 있다.The health functional food may include food supplements that are foodologically acceptable, and may include an appropriate carrier commonly used in the manufacture of health functional foods.
일 구체예에 있어서, 상기 조성물은 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.In one embodiment, the composition may contain various flavors or natural carbohydrates as additional ingredients. The natural carbohydrates include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, natural sweeteners such as thaumatin and stevia extract or synthetic sweeteners such as saccharin and aspartame can be used.
본 명세서에서 용어 "예방(prevention)"은 질환, 장애, 또는 그의 부수적 증상의 발병 또는 재발을 부분적으로 또는 완전히 지연시키거나 방지하거나, 질환 또는 장애의 획득 또는 재획득을 막거나, 질환 또는 장애의 획득의 위험을 감소시키는 것을 총칭한다. 상기 예방은 본 발명에 따른 조성물의 투여로 염증 또는 염증 관련 질환, 장애, 또는 증상의 발생을 억제 또는 지연시키는 모든 행위를 말한다.As used herein, the term “prevention” refers to partially or completely delaying or preventing the onset or recurrence of a disease, disorder, or its secondary symptoms, preventing the acquisition or re-acquisition of a disease or disorder, or preventing the development or recurrence of a disease or disorder. A general term for reducing the risk of acquisition. The prevention refers to any action that suppresses or delays the occurrence of inflammation or inflammation-related diseases, disorders, or symptoms by administering the composition according to the present invention.
본 명세서에서 용어 "개선"은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 말한다. As used herein, the term “improvement” refers to any action that results in at least a reduction in the severity of a parameter, such as a symptom, associated with the condition being treated.
본 명세서에서 용어 "치료"는 질환, 장애, 또는 그의 부수적 증상이 호전되거나 이롭게 변경되는 모든 행위를 말한다.As used herein, the term “treatment” refers to any action that improves or beneficially changes a disease, disorder, or its accompanying symptoms.
일 구체예에 있어서, 상기 조성물은 정제, 과립제, 환제, 캡슐제, 액상형, 젤리 또는 껌으로 구성되는 군으로부터 선택된 하나 이상의 제형을 갖는 것으 로서, 구강 섭취용인 것을 특징으로 한다.In one embodiment, the composition has one or more dosage forms selected from the group consisting of tablets, granules, pills, capsules, liquid forms, jelly, or gum, and is for oral intake.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 치료 또는 예방용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for the treatment or prevention of hyperuricemia or hyperuricemia-related metabolic disorders, comprising Hydrangenol, Phyllodulcin, or an acceptable salt thereof as an active ingredient.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 투여하여 고요산혈증 또는 고요산혈증 관련 대사 장애를 치료 또는 예방하는 방법을 제공한다.Another aspect provides a method of treating or preventing hyperuricemia or hyperuricemia-related metabolic disorders by administering Hydrangenol, Phyllodulcin, or an acceptable salt thereof as an active ingredient.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 잔틴산화효소(Xanthine oxidase) 저해용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for inhibiting xanthine oxidase containing Hydrangenol, Phyllodulcin, or an acceptable salt thereof as an active ingredient.
상기 고요산혈증, 고요산혈증 관련 대사 장애, 예방 또는 추출물에 대한 구체적인 내용은 전술한 바와 같다.Specific details regarding hyperuricemia, hyperuricemia-related metabolic disorders, prevention, or extracts are as described above.
본 명세서에서 용어 "치료"는 질환, 장애, 또는 그의 부수적 증상이 호전되거나 이롭게 변경되는 모든 행위를 말한다.As used herein, the term “treatment” refers to any action that improves or beneficially changes a disease, disorder, or its accompanying symptoms.
일 구체예에 있어서, 상기 조성물은 잔틴 산화효소 저해(xanthine oxidase inhibition) 작용으로 인해 혈중 또는 뇨중의 요산을 감소시켜 통풍 치료에 효과를 보이는 것일 수 있다.In one embodiment, the composition may be effective in treating gout by reducing uric acid in the blood or urine due to xanthine oxidase inhibition.
일 구체예에 있어서, 상기 조성물은 통풍으로 인한 염증을 예방하는 것일 수 있다. 상기 조성물은 잔틴 산화효소가 잔틴을 요산으로 전환시킬 때 생성되는 슈퍼옥사이드 라디칼(superoxide radical) 등을 제거하는 것일 수 있다.In one embodiment, the composition may prevent inflammation caused by gout. The composition may remove superoxide radicals, etc., which are generated when xanthine oxidase converts xanthine into uric acid.
일 구체예에 있어서, 상기 약학적 조성물은 정제, 연질 또는 경질 캡슐제, 환제, 산제, 현탁화제, 시럽제, 주사제 및 과립제로 이루어지는 군중에서 선택된 제제로 제형화된 것일 수 있다.In one embodiment, the pharmaceutical composition may be formulated with a preparation selected from the group consisting of tablets, soft or hard capsules, pills, powders, suspending agents, syrups, injections, and granules.
일 구체예에 있어서, 상기 약학적 조성물은 경구 또는 비경구 투여를 위한 것일 수 있다.In one embodiment, the pharmaceutical composition may be for oral or parenteral administration.
상기 약학적 조성물은 통상의 충진제, 증량제, 결합제, 붕해제, 항응집제, 윤활제, 습윤제, pH 조절제, 영양제, 비타민, 전해질, 알긴산 및 그의 염, 펙트산 및 그의 염, 보호성 콜로라이드, 글리세린, 향료, 유화제 또는 방부제 등을 포함할 수 있다.The pharmaceutical composition includes conventional fillers, extenders, binders, disintegrants, anti-aggregants, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectic acid and its salts, protective chloride, glycerin, It may contain fragrances, emulsifiers, or preservatives.
상기 약학적 조성물은 약학적으로 허용되는 담체를 포함할 수 있으며, 이러한 담체의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 덱스트린, 칼슘카보네이트, 프로필렌글리콜, 리퀴드 파라핀 및 생리식염수로 이루어진 군으로부터 선택된 하나 이상일 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier, examples of such carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin. , calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, It may be one or more selected from the group consisting of talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline.
상기 약학적 조성물의 제형은 사용방법에 따라 달라질 수 있으며, 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 본 발명이 속하는 기술분야에 잘 알려진 방법을 사용하여 제형화될 수 있다.The formulation of the pharmaceutical composition may vary depending on the method of use, and may be formulated using methods well known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal. It can be.
경구 투여를 위한 제제에는 정제, 연질 또는 경질 캡슐제, 환제, 산제, 현탁화제, 시럽제, 주사제 및 과립제 등이 포함되고, 이러한 제제는 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 제조될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 비경구투여를 위한 제제는 크림, 로션제, 연고제, 경고제, 액제, 에어로솔제, 유동엑스제, 엘릭서, 침제, 향낭, 패취제 또는 주사제 등일 수 있다.Preparations for oral administration include tablets, soft or hard capsules, pills, powders, suspensions, syrups, injections and granules, and these preparations may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose. It can be manufactured by mixing gelatin, etc. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Preparations for parenteral administration may be creams, lotions, ointments, warning agents, solutions, aerosols, fluid extracts, elixirs, needles, sachets, patches, or injections.
상기 방법은 임의의 동물에 적용 가능하며, 동물은 인간 및 영장류뿐 아니라, 소, 돼지, 양, 말, 개 및 고양이 등의 가축을 포함할 수 있다.The method is applicable to any animal, and the animals may include humans and primates, as well as domestic animals such as cattle, pigs, sheep, horses, dogs, and cats.
상기 치료, 예방, 또는 개선을 위한 조성물의 투여량은 투여방법, 복용자의 연령, 성별, 환자의 중증도, 상태, 체내에서 활성 성분의 흡수도, 불활성률 및 병용되는 약물을 고려하여 결정할 수 있으며, 1일 유효성분을 기준으로 하였을 때 0.1 mg/kg(체중) 내지 500 mg/kg(체중), 0.1 mg/kg(체중) 내지 400 mg/kg(체중) 또는 1 mg/kg(체중) 내지 300 mg/kg(체중)으로 투여할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있으나, 이에 한정되는 것은 아니다.The dosage of the composition for treatment, prevention, or improvement can be determined considering the method of administration, the age and gender of the recipient, the severity and condition of the patient, the absorption of the active ingredient in the body, the inactivation rate, and the concomitant drug, Based on the daily active ingredient, 0.1 mg/kg (body weight) to 500 mg/kg (body weight), 0.1 mg/kg (body weight) to 400 mg/kg (body weight), or 1 mg/kg (body weight) to 300. It can be administered in mg/kg (body weight) and can be administered once or in several divided doses, but is not limited to this.
다른 양상은 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 유효성분으로 포함하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 예방용 의약외품 조성물을 제공한다.Another aspect provides a quasi-drug composition for improving or preventing hyperuricemia or hyperuricemia-related metabolic disorders containing Hydrangenol, Phyllodulcin or an acceptable salt thereof as an active ingredient.
상기 고요산혈증, 고요산혈증 관련 대사 장애, 예방 또는 추출물에 대한 구체적인 내용은 전술한 바와 같다.Specific details regarding hyperuricemia, hyperuricemia-related metabolic disorders, prevention, or extracts are as described above.
용어 "의약외품"은 사람이나 동물의 질병을 치료, 경감, 처치 또는 예방할 목적으로 사용되는 섬유, 고무제품 또는 이와 유사한 것, 인체에 대한 작용이 약하거나 인체에 직접 작용하지 아니며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염 예방을 위하여 살균, 살충 및 이와 유사한 용도로 사용되는 제제 중 하나에 해당하는 물품으로서, 사람이나 동물의 상태 또는 질병을 진단, 치료, 경감, 처치 또는 예방할 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것 및 사람이나 동물의 구조와 기능에 약리학적 영향을 줄 목적으로 사용하는 물품 중 기구, 기계 또는 장치가 아닌 것을 제외한 물품을 의미하며, 피부 외용제 및 개인위생용품도 포함할 수 있다.The term "quasi-drug" refers to fibers, rubber products or similar products used for the purpose of treating, alleviating, treating or preventing diseases in humans or animals, have a weak effect on the human body or do not directly act on the human body, and are not instruments or machines. Products that fall under one of the following: preparations used for sterilization, insecticide, and similar purposes to prevent infection, and are used for the purpose of diagnosing, treating, alleviating, treating, or preventing the condition or disease of humans or animals. It refers to articles that are not instruments, machines, or devices, and articles used for the purpose of having a pharmacological effect on the structure and function of humans or animals, excluding those that are not instruments, machines, or devices, including external skin preparations and personal hygiene products. It can be included.
상기 추출물을 의약외품 조성물에 첨가할 경우, 상기 추출물을 그대로 첨가하거나 다른 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When adding the extract to a quasi-drug composition, the extract can be added as is or used together with other quasi-drug ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment).
상기 의약외품 조성물은 특별히 이에 제한되지 않으나, 개인위생용품, 피부외용제, 가습기 충진제, 마스크, 연고제 또는 필터충진제 등일 수 있다. 상기 개인위생용품은 비누, 물티슈, 휴지, 샴푸, 치약, 모발 손질 제품, 에어프레쉬너 겔 또는 세정 겔일 수 있다.The quasi-drug composition is not particularly limited thereto, but may be a personal hygiene product, external skin preparation, humidifier filler, mask, ointment, or filter filler. The personal hygiene products may be soap, wet tissues, toilet paper, shampoo, toothpaste, hair care products, air freshener gel, or cleaning gel.
일 양상의 조성물은 고요산혈증 또는 고요산혈증 관련 대사 장애 매개 인자인 잔틴산화효소(Xanthine Oxidase)의 활성을 저해하여 요산의 생성을 억제하고, 요산 결정으로 유발되는 염증을 완화시킴으로써, 고요산혈증 또는 고요산혈증 관련 대사 장애를 예방, 개선 및 치료하는 효과가 있다.The composition of one aspect inhibits the production of uric acid by inhibiting the activity of xanthine oxidase, a mediator of hyperuricemia or hyperuricemia-related metabolic disorders, and relieves inflammation caused by uric acid crystals. It is effective in preventing, improving and treating related metabolic disorders.
도 1은 하이드란제놀(Hydrangenol)의 ESIMS(positive-ion mode) 스펙트럼을 나타낸 도이다.
도 2는 하이드란제놀(Hydrangenol)의1H-NMR 스펙트럼을 나타낸 도이다.
도 3은 하이드란제놀(Hydrangenol)의 13C-NMR 스펙트럼을 나타낸 도이다.
도 4는 하이드란제놀(Hydrangenol)의 DEPT NMR 스펙트럼을 나타낸 도이다.
도 5는 하이드란제놀(Hydrangenol)의 HSQC NMR 스펙트럼을 나타낸 도이다.
도 6은 하이드란제놀(Hydrangenol)의 HMBC NMR 스펙트럼을 나타낸 도이다.
도 7은 필로둘신(Phyllodulcin)의 MS(positive/negative-ion mode) 스펙트럼을 나타낸 도이다.
도 8은 필로둘신(Phyllodulcin)의 1H-NMR 스펙트럼을 나타낸 도이다.
도 9는 필로둘신(Phyllodulcin)의 13C-NMR 스펙트럼을 나타낸 도이다.
도 10은 필로둘신(Phyllodulcin)의 HSQC NMR 스펙트럼을 나타낸 도이다.
도 11은 필로둘신(Phyllodulcin)의 HMBC NMR 스펙트럼을 나타낸 도이다.
도 12 는 산수국 추출물, 하이드라제놀 및 필로둘신의 잔틴산화효소 저해 활성을 나타낸 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 잔틴산화효소 저해 활성을 나타낸다.
도 13 은 산수국 추출물, 하이드라제놀 및 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 Nitric Oxide(NO) 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 NO 수치를 나타낸다.
도 14는 산수국추출물, 하이드라제놀 또는 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 IL-1β 발현 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 IL-1β 발현 수치를 나타낸다.
도 15는 산수국추출물, 하이드라제놀 또는 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 TNF-α 발현 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 TNF-α 발현 수치를 나타낸다.Figure 1 is a diagram showing the ESIMS (positive-ion mode) spectrum of Hydrangenol.
Figure 2 is a diagram showing the 1 H-NMR spectrum of Hydrangenol.
Figure 3 is a diagram showing the 13 C-NMR spectrum of Hydrangenol.
Figure 4 is a diagram showing the DEPT NMR spectrum of Hydrangenol.
Figure 5 is a diagram showing the HSQC NMR spectrum of Hydrangenol.
Figure 6 is a diagram showing the HMBC NMR spectrum of Hydrangenol.
Figure 7 is a diagram showing the MS (positive/negative-ion mode) spectrum of Phyllodulcin.
Figure 8 is a diagram showing the 1 H-NMR spectrum of Phyllodulcin.
Figure 9 is a diagram showing the 13 C-NMR spectrum of Phyllodulcin.
Figure 10 is a diagram showing the HSQC NMR spectrum of Phyllodulcin.
Figure 11 is a diagram showing the HMBC NMR spectrum of Phyllodulcin.
Figure 12 is a diagram showing the xanthine oxidase inhibitory activity of San Hydrangea extract, hydragenol, and phyllodulcine; (a) shows the xanthine oxidase inhibitory activity according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
Figure 13 is a diagram comparing Nitric Oxide (NO) levels derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea hydrangea extract, hydrazenol, and phyllodulcine; (a) shows the NO levels according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
Figure 14 is a diagram comparing IL-1β expression levels derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea hydrangea extract, hydrazenol, or phyllodulcine; (a) shows the IL-1β expression level according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
Figure 15 is a diagram comparing the expression levels of TNF-α derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea hydrangea extract, hydragenol, or phyllodulcine; (a) shows the expression level of TNF-α according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.This will be described in more detail through examples below. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
실시예 1: 산수국(Example 1: Cornus hydrangea ( Hydrangea serrataHydrangea serrata ) 추출물의 제조) Preparation of extract
일 양상의 조성물의 산수국 추출물을 제조하기 위하여, 국내에서 자생하는 산수국을 구입하여 증류수로 세척한 다음, 햇빛이 없는 서늘한 곳에서 중량의 변화가 없을 때까지 완전히 건조시켰다. 다음으로, 완전히 건조된 건조물을 균질화기를 사용하여 분쇄하여 분쇄물들을 얻은 다음 정제수 900 g을 준비한 후, 상기 분쇄물을 30 g 첨가하였다. 이때, 분쇄물과 정제수의 혼합비율은, 중량비로 30배수로 하였다. 다음으로, 상기 분쇄물과 혼합한 정제수를 항온 수조에 넣어서 100℃, 5시간 동안 교반 추출하였다. 추출된 시료는 카트리지필터(10 um)로 여과 후 감압 농축을 진행하였고, 분무 건조를 통하여 수용성 분말을 수득하였다.In order to prepare a wild hydrangea extract of one aspect of the composition, wild hydrangeas growing naturally in Korea were purchased, washed with distilled water, and then completely dried in a cool place without sunlight until there was no change in weight. Next, the completely dried product was pulverized using a homogenizer to obtain pulverized products. Then, 900 g of purified water was prepared, and then 30 g of the pulverized product was added. At this time, the mixing ratio of the ground product and purified water was 30 times the weight ratio. Next, the purified water mixed with the pulverized product was placed in a constant temperature water bath and extracted with stirring at 100°C for 5 hours. The extracted sample was filtered through a cartridge filter (10 um) and then concentrated under reduced pressure, and water-soluble powder was obtained through spray drying.
실시예 2: 하이드란제놀 및 필로둘신의 제조Example 2: Preparation of hydrangenol and phyllodulcine
2.1 하이드란제놀의 제조2.1 Preparation of hydrangenol
상기 실시예 1에서 수득한 산수국 추출 분말을 이용하여, 하이드란제놀을 제조하였다.Hydrangea extract powder obtained in Example 1 was used to prepare hydrangenol.
먼저, Diaion HP-20을 이용하여 상기 추출 분말을 겔 여과(gel filtration) 실시하였다. 전개 용매는 30%, 50%, 70%, 100% 메탄올과 CH2Cl2-MeOH(1:1, v/v)의 혼합용액을 각각 2 L씩 사용하여 용매 분획 하였으며 5개의 소분획(392-70EDia1~5)으로 나누었다. 소분획 392-70EDia4(357.4mg)는 Sephadex LH-20을 사용하였고, 메탄올을 전개용매로 하여 7개의 소분획(392-70EDia4a~4g)으로 나누었고, 이중 392-70EDia4d 분획은 메탄올에서 재결정하여 무정형의 화합물 1(Hydrangenol) 단일물질을 순수하게 수득하였다.first, The extracted powder was subjected to gel filtration using Diaion HP-20. As a developing solvent, 2 L each of a mixed solution of 30%, 50%, 70%, 100% methanol and CH2Cl2-MeOH (1:1, v/v) was used for solvent fractionation, and five small fractions (392-70EDia1~ 5) Divided into: The small fraction 392-70EDia4 (357.4mg) was divided into 7 small fractions (392-70EDia4a~4g) using Sephadex LH-20 using methanol as a developing solvent, of which the 392-70EDia4d fraction was recrystallized in methanol to form an amorphous form. Compound 1 (Hydrangenol) was obtained as a pure substance.
다음으로, 상기 화합물 1의 구조를 확인하기 위하여, ESIMS(positive-ion mode) 스펙트럼, 1H-NMR 스펙트럼, 13C-NMR 스펙트럼, DEPT NMR 스펙트럼, 2D NMR 스펙트럼 및 HMBC 스펙트럼을 측정하였다.Next, to confirm the structure of Compound 1, ESIMS (positive-ion mode) spectrum, 1 H-NMR spectrum, 13 C-NMR spectrum, DEPT NMR spectrum, 2D NMR spectrum, and HMBC spectrum were measured.
도 1는 하이드란제놀(Hydrangenol)의 ESIMS(positive-ion mode) 스펙트럼을 나타낸 도이다.Figure 1 is a diagram showing the ESIMS (positive-ion mode) spectrum of Hydrangenol.
도 2는 하이드란제놀(Hydrangenol)의1H-NMR 스펙트럼을 나타낸 도이다.Figure 2 is a diagram showing the 1 H-NMR spectrum of Hydrangenol.
도 3은 하이드란제놀(Hydrangenol)의 13C-NMR 스펙트럼을 나타낸 도이다.Figure 3 is a diagram showing the 13 C-NMR spectrum of Hydrangenol.
도 4는 하이드란제놀(Hydrangenol)의 DEPT NMR 스펙트럼을 나타낸 도이다.Figure 4 is a diagram showing the DEPT NMR spectrum of Hydrangenol.
도 5는 하이드란제놀(Hydrangenol)의 HSQC NMR 스펙트럼을 나타낸 도이다.Figure 5 is a diagram showing the HSQC NMR spectrum of Hydrangenol.
도 6은 하이드란제놀(Hydrangenol)의 HMBC NMR 스펙트럼을 나타낸 도이다.Figure 6 is a diagram showing the HMBC NMR spectrum of Hydrangenol.
그 결과, 도 1 및 2에 나타낸 것과 같이, ESIMS(positive-ion mode) 스펙트럼의 경우 m/z = 257 [M+H]+로 나타났고, 1H-NMR스펙트럼의 경우 고자장에서 나타나는 δH 5.50에서의 methine proton(H-3)과 δH3.30과 3.06에서의 methylene proton(H-4)이 서로 vicinal coupling한다는 점과 chemical shift 값으로 C ring에서 기인하는 proton임을 확인하였다. 더불어, B-ring의 p-substituted benzene ring에서 기인하는 H-2', H-3'과 H-6' H-5'은 서로 ortho coupling하여 doublet(J = 8.4 Hz)으로 나타나고, H-2'과 H-6'의 피크와 H-3'과 H-5'의 피크들도 서로 ortho coupling을 하여 doublet으로 나타나 hydroxy기를 중심으로 서로 대칭구조임을 알 수 있었다. 또한, A-ring의 1,2,3-trisubstituted benzene에서는 H-5와 H-7번 수소는 각각 H-6 수소와 coupling하여 H-5와 H-7번 수소는 ortho coupling으로 doublet, H-6 proton은 ortho 와 meta coupling으로 double of doublets로 나타나며, 모두 하나의 수소에 해당하는 피크임을 알 수 있었다.As a result, as shown in Figures 1 and 2, the ESIMS (positive-ion mode) spectrum showed m/z = 257 [M+H]+, and the 1 H-NMR spectrum showed δH 5.50 at a high magnetic field. It was confirmed that the methine proton (H-3) at and the methylene proton (H-4) at δH3.30 and 3.06 were vicinal coupled to each other and that the proton originated from the C ring through the chemical shift value. In addition, H-2', H-3' and H-6' and H-5' resulting from the p-substituted benzene ring of the B-ring are ortho coupled to each other and appear as a doublet (J = 8.4 Hz), and H-2 The peaks of ' and H-6' and the peaks of H-3' and H-5' were ortho-coupled with each other and appeared as doublets, showing that they had a symmetrical structure around the hydroxy group. In addition, in the 1,2,3-trisubstituted benzene of the A-ring, hydrogens H-5 and H-7 are coupled with hydrogen H-6, respectively, and hydrogens H-5 and H-7 are ortho coupled to doublet, H- 6 Protons appear as doubles of doublets due to ortho and meta coupling, and it was found that all peaks correspond to one hydrogen.
또한, 도 3 및 4에 나타낸 것과 같이, 13C-NMR스펙트럼의 경우 para-치환체를 포함하여 총 15개의 피크를 나타냄을 확인하였다. δC 172에서의quarternary 탄소는 화합물 1번 탄소인 carbonyl group에서 기인한 피크이며, δC 116.9(C-3', C-5')과 129.6(C-2', C-6')는 aromatic ring의 파라 치환체에서 기인한 피크이며, δC 36.1과 83.1의 피크는 각각 aliphatic carbon과 oxygenated carbon에서 기인한 것으로 예상되었다. 또한 DEPT NMR스펙트럼의 경우, 7개의 protonated carbons을 확인할 수 있었으며, δC 36.1의 피크는 C-4에서 기인한 methylene group임을 알 수 있었다.In addition, as shown in Figures 3 and 4, it was confirmed that the 13 C-NMR spectrum showed a total of 15 peaks, including the para-substituent. The quarternary carbon at δC 172 is a peak resulting from the carbonyl group, carbon number 1 of the compound, and δC 116.9 (C-3', C-5') and 129.6 (C-2', C-6') are the peaks of the aromatic ring. It is a peak originating from the para substituent, and the peaks at δC 36.1 and 83.1 were expected to originate from aliphatic carbon and oxygenated carbon, respectively. Additionally, in the case of the DEPT NMR spectrum, seven protonated carbons were identified, and the peak at δC 36.1 was found to be a methylene group originating from C-4.
더불어 도 5 및 6에 따르면, 2D NMR로 화합물 1의 정확한 구조를 확인할 수 있었으며, HSQC스펙트럼으로부터 피크들의 정확한 위치를 동정하여 HMBC로부터 치환기가 결합된 위치를 알 수 있었다. 즉, δH 7.26(2H, d,J = 8.4 Hz, H-2' H-6')의 피크는 δC 36.1의 C-4와 상관관계가 나타나고 H-4에서 기인한 δH 3.06과 3.30의 피크들은 δC 83.1(C-3), 119.8(C-5), 110.0(C-9), 142.2(C-10)의 피크와 상관관계가 나타났다.In addition, according to Figures 5 and 6, the exact structure of Compound 1 could be confirmed by 2D NMR, and the exact positions of the peaks were identified from the HSQC spectrum to determine the position where the substituent was bound from HMBC. In other words, the peak at δH 7.26 (2H, d,J = 8.4 Hz, H-2' H-6') is correlated with C-4 at δC 36.1, and the peaks at δH 3.06 and 3.30 resulting from H-4 are A correlation was found with peaks of δC of 83.1 (C-3), 119.8 (C-5), 110.0 (C-9), and 142.2 (C-10).
상기와 같은 점을 종합하여, 공지 문헌을 참고해 화합물 1이 하이드란제놀(Hydrangenol)이라는 것을 확인하였다(Yoshikawa M.,Matsuda H., Shimoda H., Shimada H., Harada E., Naitoh Y., Miki A., Yamahara J., Murakami N.Development of Bioactive Functions in Hydrangeae Dulcis Folium. V. On the Antiallergic and Antimicrobial Principles of Hydrangeae Dulcis Folium. (2). Thunberginols C, D, and E, Thunberginol G 3'-O-Glucoside, (-)-Hydrangenol 4'-O-Glucoside, and (+)-Hydrangenol 4'-O-Glucoside. Chem. Pharm. Bull.1996, 44: 1440-1447).Taking the above points into account, and referring to known literature, it was confirmed that Compound 1 was Hydrangenol (Yoshikawa M., Matsuda H., Shimoda H., Shimada H., Harada E., Naitoh Y., Miki A., Yamahara J., Murakami N.Development of Bioactive Functions in Hydrangeae Dulcis Folium. V. On the Antiallergic and Antimicrobial Principles of Hydrangeae Dulcis Folium. (2). Thunberginols C, D, and E, Thunberginol G 3'- O-Glucoside, (-)-Hydrangenol 4'-O-Glucoside, and (+)-Hydrangenol 4'-O-Glucoside. Chem. Pharm. Bull. 1996, 44: 1440-1447).
2.2 필로둘신 제조2.2 Philodulcine production
상기 실시예 1에서 수득한 산수국 추출 분말을 이용하여, 필로둘신을 제조하였다.Phylodulcine was prepared using the Hydrangea hydrangea extract powder obtained in Example 1 above.
먼저, Diaion HP-20을 이용하여 상기 추출 분말을 겔 여과(gel filtration)하였다. 전개용매는 30%, 50%, 70%, 100% 메탄올과 CH2Cl2-MeOH(1:1, v/v)의 혼합용액을 각각 2 L씩 사용하여 용매분획 하였으며 5개의 소분획(Fr. 1~5)으로 나누었다. 소분획 Fr.4 는 Sephadex LH-20을 사용하여 메탄올을 전개용매로 하여 7개의 소분획(Fr.4-1~7)으로 나누었고, 이중 Fr.4-3 분획은 메탄올에서 재결정하여 무정형의 화합물 2(phyllodulcin) 단일물질을 순수하게 수득하였다. First, the extracted powder was subjected to gel filtration using Diaion HP-20. As a developing solvent, 2 L each of a mixed solution of 30%, 50%, 70%, and 100% methanol and CH2Cl2-MeOH (1:1, v/v) was used for solvent fractionation, and five small fractions (Fr. 1~ 5) Divided into: Sub-fraction Fr.4 was divided into 7 sub-fractions (Fr.4-1 to 7) using Sephadex LH-20 using methanol as a developing solvent, of which Fr.4-3 fraction was recrystallized in methanol to form an amorphous compound. 2 (phyllodulcin) was obtained as a single substance in pure form.
다음으로, 상기 화합물 2의 구조를 확인하기 위하여, MS(positive/negative-ion mode) 스펙트럼, 1H-NMR 스펙트럼, 13C-NMR 스펙트럼, HSQC 스펙트럼 및 HMBC 스펙트럼을 측정하였다.Next, to confirm the structure of Compound 2, the MS (positive/negative-ion mode) spectrum, 1 H-NMR spectrum, 13 C-NMR spectrum, HSQC spectrum, and HMBC spectrum were measured.
도 7은 필로둘신(Phyllodulcin)의 MS(positive/negative-ion mode) 스펙트럼을 나타낸 도이다.Figure 7 is a diagram showing the MS (positive/negative-ion mode) spectrum of Phyllodulcin.
도 8은 필로둘신(Phyllodulcin)의 1H-NMR 스펙트럼을 나타낸 도이다.Figure 8 is a diagram showing the 1 H-NMR spectrum of Phyllodulcin.
도 9는 필로둘신(Phyllodulcin)의 13C-NMR 스펙트럼을 나타낸 도이다.Figure 9 is a diagram showing the 13 C-NMR spectrum of Phyllodulcin.
도 10은 필로둘신(Phyllodulcin)의 HSQC NMR 스펙트럼을 나타낸 도이다.Figure 10 is a diagram showing the HSQC NMR spectrum of Phyllodulcin.
도 11은 필로둘신(Phyllodulcin)의 HMBC NMR 스펙트럼을 나타낸 도이다.Figure 11 is a diagram showing the HMBC NMR spectrum of Phyllodulcin.
그 결과, 도 7 및 8에 나타낸 것과 같이, 상기 LC-MS(negative-ion mode) 스펙트럼의 경우 m/z = 285 [M-H]-임을 확인하였고, 1H-NMR스펙트럼의 경우, 고자장에서 나타나는 δH 5.65에서의 methine proton(H-3)과 δH 3.34과 3.16에서의 methylene proton(H-4)이 서로 vicinal coupling한다는 점과 chemical shift 값으로 C ring에서 기인하는 proton임을 확인하였다.As a result, as shown in Figures 7 and 8, in the case of the LC-MS (negative-ion mode) spectrum, it was confirmed that m/z = 285 [MH]-, and in the case of the 1 H-NMR spectrum, it appeared at a high magnetic field. It was confirmed that the methine proton (H-3) at δH 5.65 and the methylene proton (H-4) at δH 3.34 and 3.16 were vicinal coupled to each other and that the proton originated from the C ring through the chemical shift value.
구체적으로, B-ring의 p-substituted benzene ring에서 기인하는 H-2'은 H-6'와 서로 meta coupling하여 doublet(J = 2.4 Hz, δH 6.95)으로 나타나고, H-6' 피크는 H-2', H-3' 피크들과 각각 mata, ortho coupling을 하여 double of doublets(J = 2.4,8.4 Hz, δH 6.90)으로 나타나며, H-5'은 H-6'와 서로 ortho coupling하여 doublet(J = 8.4 Hz, δH 6.96)으로 나타나는 것으로 볼 때 ABX system으로 치환된 구조임을 알 수 있었다. δH 3.91 에서 methoxy로 추정되는 singlet의 수소 3개가 확인됨을 알 수 있었다.Specifically, H-2' resulting from the p-substituted benzene ring of the B-ring meta-couples with H-6' to appear as a doublet (J = 2.4 Hz, δH 6.95), and the H-6' peak is H-6'. It appears as a double of doublets (J = 2.4,8.4 Hz, δH 6.90) through mata and ortho coupling with the 2' and H-3' peaks, respectively, and H-5' is ortho coupled with H-6' to form a doublet ( J = 8.4 Hz, δH 6.96), it was found that the structure was replaced by the ABX system. At δH 3.91, three hydrogens of a singlet, presumed to be methoxy, were confirmed.
또한, A-ring의 1,2,3-trisubstituted benzene에서는 H-5와 H-7번 수소는 각각 H-6 수소와 coupling하여 H-5와 H-7번 수소는 ortho coupling으로 doublet, H-6 proton은 H-5, H-7번 수소와 ortho coupling으로 triplets로 나타나며, 모두 하나의 수소에 해당하는 피크임을 알 수 있었다.In addition, in the 1,2,3-trisubstituted benzene of the A-ring, hydrogens H-5 and H-7 are coupled with hydrogen H-6, respectively, and hydrogens H-5 and H-7 are ortho coupled to doublet, H- 6 protons appear as triplets due to ortho coupling with hydrogens H-5 and H-7, and it was found that all peaks correspond to one hydrogen.
더불어, 도 9 에 나타낸 것과 같이, 13C-NMR 스펙트럼은 para-치환체를 포함하여 총 16개의 피크가 나타났으며, δC 169.3에서의 quarternary 탄소는 화합물 1번 탄소인 carbonyl group에서 기인한 피크이고, δC 55.6 에서의 탄소는 methoxy group에서 기인한 피크이며, δC 33.6과 80.2의 피크는 각각 aliphatic carbon과 oxygenated carbon에서 기인하였음을 예상하였다.In addition, as shown in Figure 9, the 13 C-NMR spectrum showed a total of 16 peaks including para-substituents, and the quarternary carbon at δC 169.3 is a peak resulting from the carbonyl group, which is carbon number 1 of the compound, It was expected that the carbon at δC 55.6 peak originated from a methoxy group, and the peaks at δC 33.6 and 80.2 were expected to originate from aliphatic carbon and oxygenated carbon, respectively.
더불어, 도 10 내지 11 에 나타낸 것과 같이, 2D NMR을 분석 시 HSQC 스펙트럼으로 피크들의 정확한 위치를 동정할 수 있었으며, HMBC 스펙트럼으로 치환기가 결합된 위치를 확인하였다.In addition, as shown in Figures 10 and 11, when analyzing 2D NMR, the exact positions of the peaks could be identified through the HSQC spectrum, and the position at which the substituent was bound was confirmed through the HMBC spectrum.
상기와 같은 점을 종합하여, 공지 문헌을 참고해 화합물 2가 필로둘신(phyllodulcin)이라는 것을 확인하였다(Mandal, S. K., & Roy, S. C. Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of(±)-hydrangenol,(±)-phyllodulcin, (±)-macrophyllol and(±)-thunberginol G, Tetrahedron. 2008, 64(49): 11050-11057).Taking the above points into account, it was confirmed that Compound 2 was phyllodulcin with reference to known literature (Mandal, S. K., & Roy, S. C. Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of(±)-hydrangenol,(±)-phyllodulcin, (±)-macrophyllol and(±)-thunberginol G, Tetrahedron. 2008, 64(49): 11050-11057).
실험예 1: 산수국 추출물의 총 폴리페놀(TPC) 함량 분석Experimental Example 1: Analysis of total polyphenol (TPC) content of San Hydrangea extract
상기 실시예 1 추출물의 고요산혈증 또는 고요산혈증 관련 대사 장애의 치료 또는 개선 효과를 확인하기 위하여, 산수국 추출물의 총 폴리페놀 함량 분석을 수행하였다.In order to confirm the effectiveness of the extract of Example 1 in treating or improving hyperuricemia or hyperuricemia-related metabolic disorders, analysis of the total polyphenol content of the extract of Wild Hydrangea was performed.
먼저, 10 mg/ml의 농도로 용해한 산수국 추출물 20 ㎕에 20% 폴린-시오칼토(Folin-Ciocalteau)시약 및 10 % 탄산 나트륨(Na2CO3)용액을 혼합하고, 140㎕ 및 dH2O 20㎕를 차례로 가하여 상온에서 30분간 반응시킨 후, 765 ㎚에서 흡광도를 측정하였다.First, 20 ㎕ of Hydrangea extract dissolved at a concentration of 10 mg/ml was mixed with 20% Folin-Ciocalteau reagent and 10% sodium carbonate (Na 2 CO 3 ) solution, and 140 ㎕ and dH 2 O were mixed. 20㎕ was sequentially added and reacted at room temperature for 30 minutes, and then the absorbance was measured at 765 nm.
총 폴리페놀 함량은 갈릭산(Gallic Acid)을 표준물질로 정하여 측정한 흡광도를 이용해, 으로 작성한 검량선으로부터 계산하였다. 폴리페놀의 함량 단위는 (mg GAE/g)이다.The total polyphenol content is determined using the absorbance measured using gallic acid as a standard substance. It was calculated from the calibration curve prepared by . The unit of polyphenol content is (mg GAE/g).
표 1은 산수국 추출물의 폴리페놀 함량을 농도별로 나타낸 표이다.Table 1 is a table showing the polyphenol content of San Hydrangea extract by concentration.
(mg GAE/g)mountain hydrangea
(mg GAE/g)
그 결과, 표 1에 나타낸 것과 같이, 산수국 추출물은 높은 함량의 폴리페놀을 포함하고 있음을 확인하였다. 상기와 같은 결과는, 일 양상의 조성물이 항염 및 항산화 효과가 높은 폴리페놀을 풍부히 포함하여 요산 수치를 낮춰줌으로써, 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 현저함을 의미하는 것이다.As a result, as shown in Table 1, it was confirmed that the San Hydrangea extract contained a high content of polyphenol. The above results mean that the composition of one aspect contains an abundance of polyphenols with high anti-inflammatory and antioxidant effects, thereby lowering uric acid levels, thereby significantly improving or treating hyperuricemia or hyperuricemia-related metabolic disorders.
실험예 2: 산수국 추출물의 총 플라보노이드 (TFC) 함량 분석Experimental Example 2: Analysis of total flavonoid (TFC) content of San Hydrangea extract
상기 실시예 1 추출물의 고요산혈증 또는 고요산혈증 관련 대사 장애의 치료 또는 개선 효과를 확인하기 위하여, 각 추출물의 총 플라보노이드 함량 분석을 수행하였다.In order to confirm the effectiveness of the extract of Example 1 in treating or improving hyperuricemia or hyperuricemia-related metabolic disorders, analysis of the total flavonoid content of each extract was performed.
우선, 10 mg/ml의 농도로 용해한 각 추출물 20 ㎕에 5% 아질산나트륨 용액(NaNO2) 10㎕를 혼합하여 5분간 반응시키고, 염화알루미늄 용액(AlCl3) 100㎕를 첨가하여 5 분간 방치하였다. 다음으로, 1 M 수산화나트륨(NaOH) 50 ㎕와 섞어 10 분간 반응시킨 후, 765 ㎚에서 흡광도를 측정하였다.First, 20 ㎕ of each extract dissolved at a concentration of 10 mg/ml was mixed with 10 ㎕ of 5% sodium nitrite solution (NaNO 2 ) and reacted for 5 minutes. 100 ㎕ of aluminum chloride solution (AlCl 3 ) was added and left for 5 minutes. . Next, it was mixed with 50 ㎕ of 1 M sodium hydroxide (NaOH) and reacted for 10 minutes, and then the absorbance was measured at 765 nm.
총 플라보노이드 함량은 (mg Catechin/g)을 표준물질로 정하여 으로 작성한 검량선으로부터 계산하였다. The total flavonoid content was determined as (mg Catechin/g) as the standard substance. It was calculated from the calibration curve prepared by .
표 2는 실시예 1의 산수국 추출물의 플라보노이드 함량을 농도별로 나타낸 표이다.Table 2 is a table showing the flavonoid content of the San Hydrangea extract of Example 1 by concentration.
(mg Catechin/g)mountain hydrangea
(mg Catechin/g)
그 결과, 표 2에 나타낸 바와 같이, 산수국 추출물은 높은 함량의 플라보노이드를 포함하고 있었다. 상기와 같은 결과는, 일 양상의 조성물이 플라보노이드를 풍부히 포함하여 요산 수치를 낮춰줌으로써, 현저한 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 있음을 의미하는 것이다.As a result, as shown in Table 2, the San Hydrangea extract contained a high content of flavonoids. The above results mean that the composition of one aspect is rich in flavonoids and lowers uric acid levels, thereby improving or treating significant hyperuricemia or hyperuricemia-related metabolic disorders.
실험예 3: 산수국 추출물의 DPPH 라디칼 소거능 확인Experimental Example 3: Confirmation of DPPH radical scavenging ability of San Hydrangea extract
상기 실시예 1의 산수국 추출물의 유리기(free radical) 억제능을 확인하기 위하여, 각 추출물의 2,2-디페닐-1-피크릴하이드라질(DPPH) 라디칼 소거능을 확인하였다.In order to confirm the free radical inhibition ability of the Hydrangea extract of Example 1, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability of each extract was confirmed.
우선, 2,2-디페닐-1- 피크릴하이드라질 시약 19.716 mg과 80%의 에탄올 500 ml를 섞어 0.1 mM의 DPPH 시약을 제조하였다. 다음으로, 적절한 농도의 시료와 DPPH 시약을 30분간 실온에서 반응시킨 후, 517 nm에서 흡광도를 측정하였다. 측정한 흡광도를 사용하여, DPPH 라디칼 소거능(%)을 으로 계산하였다.First, 0.1 mM DPPH reagent was prepared by mixing 19.716 mg of 2,2-diphenyl-1-picrylhydrazyl reagent with 500 ml of 80% ethanol. Next, the sample at an appropriate concentration and the DPPH reagent were reacted at room temperature for 30 minutes, and then the absorbance was measured at 517 nm. Using the measured absorbance, the DPPH radical scavenging ability (%) was determined. It was calculated as .
표 3은 실시예 1의 산수국 추출물의 2,2-디페닐-1-피크릴하이드라질(DPPH) 라디칼 소거능을 나타낸 표이다.Table 3 is a table showing the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability of the Hydrangea extract of Example 1.
(%)mountain hydrangea
(%)
그 결과, 표 3에 나타낸 바와 같이, 실시예 1의 산수국 추출물은 높은 함량의 DPPH 라디칼 소거능이 있었다. 상기와 같은 결과는, 일 양상의 조성물의 라디칼 소거능이 우수함으로서, 유리기(free radical) 억제능이 뛰어나 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료에 효과가 있음을 의미하는 것이다.As a result, as shown in Table 3, the San Hydrangea extract of Example 1 had a high content of DPPH radical scavenging ability. The above results mean that the composition in one aspect has excellent radical scavenging ability, and therefore has excellent free radical inhibition ability, and is consequently effective in improving or treating hyperuricemia or hyperuricemia-related metabolic disorders.
실험예 4: 산수국 추출물의 초과산화물불균등화효소(Superoxide dismutase: SOD)Experimental Example 4: Superoxide dismutase (SOD) of wild hydrangea extract 활성 확인active check
상기 실시예 1의 산수국 추출물의 초과산화물불균등화효소(Superoxide dismutase: SOD) 활성을 확인하기 위하여, SOD Determination kit(Sigma, MO, USA) 를 이용하였다.To confirm the superoxide dismutase (SOD) activity of the Hydrangea extract of Example 1, a SOD Determination kit (Sigma, MO, USA) was used.
구체적으로, 상기 실시예1의 산수국 추출물을 각각 희석한 후 20 ㎕씩 96 웰 플레이트에 분주하고, 200 ㎕의 WST(Water-soluble tetrazolium salt) 용액과 20 ㎕의 효소반응 액을 첨가하였다. 다음으로, 웰 플레이트를 37 ℃에서 20분 처리 한 후, microplate reader(BioTek, VT, USA)를 이용하여 450 nm에서 흡광도를 측정하였다. 측정한 흡광도를 이용하여, SOD 효소 활성률을 ) 으로 계산하였다.Specifically, the San Hydrangea extract of Example 1 was diluted and distributed in 20 ㎕ portions into 96 well plates, and 200 ㎕ WST (Water-soluble tetrazolium salt) solution and 20 ㎕ enzyme reaction solution were added. Next, the well plate was treated at 37°C for 20 minutes, and then the absorbance was measured at 450 nm using a microplate reader (BioTek, VT, USA). Using the measured absorbance, the SOD enzyme activity rate was determined. ) was calculated.
표 4는 실시예 1의 산수국 추출물의 SOD 효소 활성률을 농도 별로 나타낸 표이다.Table 4 is a table showing the SOD enzyme activity rate of the Hydrangea extract of Example 1 by concentration.
(%)mountain hydrangea
(%)
그 결과, 표 4에 나타낸 것과 같이, 실시예 1의 산수국 추출물은 SOD 효소 활성도가 우수함을 확인하였다.As a result, as shown in Table 4, it was confirmed that the San Hydrangea extract of Example 1 had excellent SOD enzyme activity.
상기와 같은 결과는 SOD가 초과 산화이온을 산소와 과산화수소로 바꿔 주는 불균등화 반응을 촉매함으로서, 체내에 쌓인 과잉의 활성산소를 제거하여 통풍 염증 및 통증을 완화할 수 있으므로, 일 양상의 조성물의 경우 높은 SOD 효소 활성도로 인해 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료에 효과가 있음을 의미하는 것이다.The above result is that SOD catalyzes a disproportionation reaction that changes excess oxide ions into oxygen and hydrogen peroxide, thereby removing excess oxygen radicals accumulated in the body and relieving gout inflammation and pain. In the case of one aspect of the composition, This means that due to the high SOD enzyme activity, it is effective in improving or treating hyperuricemia or hyperuricemia-related metabolic disorders.
실험예 5. 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염 처리 시 잔틴산화효소 저해 확인Experimental Example 5. Confirmation of inhibition of xanthine oxidase when treated with Hydrangea extract or hydrangenol, phyllodulcin, or their acceptable salts derived therefrom.
상기 실시예 1의 산수국 추출물 및 실시예 2.1의 하이드란제놀과 실시예 2.2의 필로둘신의 잔틴산화효소 저해 활성을 확인하기 위하여, Xanthine oxidase assay kit(AAT Bioquest, CA, USA)를 이용하였다.To confirm the xanthine oxidase inhibitory activity of the Hydrangea extract of Example 1, hydrangenol of Example 2.1, and phyllodulcine of Example 2.2, a Xanthine oxidase assay kit (AAT Bioquest, CA, USA) was used.
상기 실시예 1의 산수국 추출물 및 실시예 2.1의 하이드란제놀과 실시예 2.2의 필로둘신과 잔틴산화효소를 Amplite Red 희석액, Horseradish Peroxidase 희석액 및 잔틴 희석액과 혼합한 뒤 상온의 암실에서 30 내지 60분동안 처리하였다. 다음으로, 570/610 nm에서 마이크로플레이트 리더(microplate reader)로 흡광도를 측정하고, 상기 측정된 흡광도를 를 이용하여 XOD 활성(XOD activity)을 계산하였다. The Hydrangea extract of Example 1, the hydrangenol of Example 2.1, and the phyllodulcin and xanthine oxidase of Example 2.2 were mixed with Amplite Red dilution, Horseradish Peroxidase dilution, and xanthine dilution and then kept in a dark room at room temperature for 30 to 60 minutes. processed for a while. Next, measure the absorbance at 570/610 nm with a microplate reader, and the measured absorbance is XOD activity was calculated using .
도 12 는 산수국 추출물, 하이드라제놀 및 필로둘신의 잔틴산화효소 저해 활성을 나타낸 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 잔틴산화효소 저해 활성을 나타낸다.Figure 12 is a diagram showing the xanthine oxidase inhibitory activity of San Hydrangea extract, hydragenol, and phyllodulcine; (a) shows the xanthine oxidase inhibitory activity according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
그 결과, 도 12에 나타낸 것과 같이, 산수국 추출물, 하이드라제놀 또는 필로둘신을 포함하는 조성물 모두 유의적으로 잔틴산화효소를 저해함을 확인할 수 있었다. 잔틴산화효소는 요산과 과산화물로의 산화를 촉진하기 때문에, 상기와 같은 결과는 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 포함하는 조성물의 경우 높은 잔틴산화효소 저해능으로 인해 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 있음을 의미하는 것이다.As a result, as shown in Figure 12, it was confirmed that all compositions containing Hydrangea hydrangea extract, hydrazenol, or phyllodulcine significantly inhibited xanthine oxidase. Since xanthine oxidase promotes the oxidation of uric acid and peroxide, the above results are obtained in a composition containing Hydrangea extract or hydrangenol, phyllodulcin, or acceptable salts thereof derived therefrom. In the case of , this means that there is an improvement or treatment effect on hyperuricemia or hyperuricemia-related metabolic disorders due to the high xanthine oxidase inhibitory ability.
실험예 6. 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염 처리 시 MSU(Monosodium urate) crystals로 유래된 Nitric Oxide(NO) 감소 확인Experimental Example 6. Confirmation of reduction of Nitric Oxide (NO) derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea extract or Hydrangenol, Phyllodulcin or their acceptable salts derived therefrom.
상기 실시예 1의 산수국 추출물 및 실시예 2.1의 하이드란제놀과 실시예 2.2의 필로둘신의 산화질소(Nitric Oxide: NO)의 감소 효과를 확인하기 위하여, MSU(Monosodium urate) crystals로 염증 반응을 일으킨 후 NO의 변화를 확인하였다.In order to confirm the effect of reducing nitric oxide (NO) of the Hydrangea extract of Example 1, hydrangenol of Example 2.1, and phyllodulcine of Example 2.2, the inflammatory response was measured with MSU (Monosodium urate) crystals. After this, changes in NO were confirmed.
먼저, American Type Culture Collection(ATCC, MD, USA)로부터 수득한 대식세포인 RAW264.7 세포를 10% FBS 및 1% antibiotic-antimycotic가 포함된 DMEM 배지에서 5% CO2, 37℃ 에서 배양하였다. 다음으로, 배양한 세포를 6 웰 플레이트에 1.0 × 106 cells/2 ㎖/well 의 농도로 24 시간 동안 부착시킨 후 DMEM 에 1 ㎎/ml MSU(Monosodium urate) crystals 및 실시예 1 및 2.1과 2.2를 각각의 농도로 처리하여 24 시간 동안 배양하였다. 다음으로, 배양 상등액을 100 ㎕씩 96 웰 플레이트에 분주한 후, Griess(0.1% N-(1-naphtyl) ethylenediamine, 1% sulfanilamide) 시약 100 ㎕ 혼합하고 10 분 동안 반응시킨 뒤, 발색 azo-유도체 분자의 흡광도를 540 nm 에서 마이크로플레이트 리더(microplate reader, BioTek, Vermont, USA)로 측정하였다. 측정한 흡광도를 이용하여, 아질산 나트륨의 희석 범위를 각 샘플의 아질산염의 양으로 표준 곡선 변환하여 NO 분비량을 계산하였다.First, RAW264.7 cells, which are macrophages obtained from the American Type Culture Collection (ATCC, MD, USA), were cultured at 37°C in 5% CO 2 in DMEM medium containing 10% FBS and 1% antibiotic-antimycotic. Next, the cultured cells were attached to a 6- well plate at a concentration of 1.0 were treated with each concentration and cultured for 24 hours. Next, 100 ㎕ of the culture supernatant was dispensed into 96 well plates, mixed with 100 ㎕ of Griess (0.1% N-(1-naphtyl) ethylenediamine, 1% sulfanilamide) reagent, reacted for 10 minutes, and colored with azo-derivative. The absorbance of the molecule was measured at 540 nm with a microplate reader (BioTek, Vermont, USA). Using the measured absorbance, the dilution range of sodium nitrite was converted to a standard curve to the amount of nitrite in each sample to calculate the amount of NO secretion.
도 13 은 산수국 추출물, 하이드라제놀 또는 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 Nitric Oxide(NO) 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 NO 수치를 나타낸다.Figure 13 is a diagram comparing Nitric Oxide (NO) levels derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea extract, hydrazenol, or phyllodulcine; (a) shows the NO levels according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
그 결과, 도 13에 나타낸 것과 같이, 산수국 추출물, 하이드라제놀 또는 필로둘신을 포함하는 조성물 모두 유의적으로 NO 분비를 저해함을 확인할 수 있었다. 상기와 같은 결과는 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 포함하는 조성물의 경우 높은 NO 분비를 저해 효과로 인해 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 있음을 의미하는 것이다.As a result, as shown in Figure 13, it was confirmed that all compositions containing Hydrangea hydrangea extract, hydrazenol, or phyllodulcine significantly inhibited NO secretion. The above results show that compositions containing Hydrangea extract or hydrangenol, phyllodulcin, or acceptable salts thereof derived therefrom have the effect of inhibiting high NO secretion, resulting in hyperuricemia or hyperuricemia. This means that there is an improvement or treatment effect on hyperuricemia-related metabolic disorders.
실험예 7: 산수국 추출물 또는 이로부터 유래하는 하이드란제놀 (hydrangenol) 또는 필로둘신 (Phyllodulcin) 처리 시 MSU(Monosodium urate) crystals로 유래된 IL-1β 발현 감소 확인Experimental Example 7: Confirmation of decreased expression of IL-1β derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea extract or hydrangenol or Phyllodulcin derived therefrom
상기 실시예 1의 산수국 추출물 및 실시예 2.1의 하이드란제놀과 실시예 2.2의 필로둘신에 대하여 MSU(Monosodium urate) crystals로 염증 반응을 일으킨 후, IL-1β의 발현량을 ELISA kit를 이용하여 확인하였다.After causing an inflammatory response to the Hydrangea extract of Example 1, hydrangenol of Example 2.1, and phyllodulcine of Example 2.2 with MSU (Monosodium urate) crystals, the expression level of IL-1β was measured using an ELISA kit. Confirmed.
구체적으로, 대식세포인 RAW264.7 세포는 American Type Culture Collection (ATCC, MD, USA)로부터 수득하였으며, 10% FBS 및 1% antibiotic-antimycotic가 포함된 DMEM 배지에서 5% CO2, 37℃ 에서 배양하였다. RAW264.7 세포를 6 웰 플레이트에 1.0 × 106 cells/ 2 ㎖/well 의 농도로 24 시간 동안 부착시킨 후 DMEM 에 1 ㎎/ml MSU(Monosodium urate) crystals와 실시예 1 및 2를 각각의 농도로 처리하여 24 시간 동안 배양하였다. 24시간 후 배양 배지를 원심 분리하여 얻어진 상층액의 IL-1β를 ELISA kit를 이용하여 정량하였다.Specifically, RAW264.7 cells, which are macrophages, were obtained from the American Type Culture Collection (ATCC, MD, USA) and cultured at 37°C in 5% CO 2 in DMEM medium containing 10% FBS and 1% antibiotic-antimycotic. did. RAW264.7 cells were attached to a 6- well plate at a concentration of 1.0 treated with and cultured for 24 hours. After 24 hours, the culture medium was centrifuged and IL-1β in the obtained supernatant was quantified using an ELISA kit.
도 14는 산수국추출물, 하이드라제놀 또는 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 IL-1β 발현 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 IL-1β 발현 수치를 나타낸다.Figure 14 is a diagram comparing the expression levels of IL-1β derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea hydrangea extract, hydrazenol, or phyllodulcine; (a) shows the IL-1β expression level according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
그 결과 도 14 에 도시된 것과 같이. 산수국 추출물 또는 이로부터 유래하는 하이드란제놀 (Hydrangenol) 또는 필로둘신 (Phyllodulcin)은 유의적으로 IL-1β 발현을 저해하였다. 상기와 같은 결과는 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 포함하는 조성물의 경우 높은 IL-1β 발현을 저해 효과로 인해 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 있음을 의미하는 것이다.As a result, as shown in Figure 14. Hydrangea extract or hydrangenol or phyllodulcin derived therefrom significantly inhibited IL-1β expression. The above results result from the inhibitory effect on high IL-1β expression in the case of compositions containing Hydrangea extract or hydrangenol, phyllodulcin, or acceptable salts thereof derived therefrom. This means that there is an improvement or treatment effect on metabolic disorders related to acidemia or hyperuricemia.
실험예 8: 산수국 추출물 또는 이로부터 유래하는 하이드란제놀 (hydrangenol) 또는 필로둘신 (Phyllodulcin) 처리 시 MSU(Monosodium urate) crystals로 유래된 TNF-α 발현 감소 확인Experimental Example 8: Confirmation of decreased expression of TNF-α derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea extract or hydrangenol or Phyllodulcin derived therefrom
상기 실시예 1의 산수국 추출물 및 실시예 2.1의 하이드란제놀과 실시예 2.2의 필로둘신에 대하여 MSU(Monosodium urate) crystals로 염증 반응을 일으킨 후, TNF-α의 발현량을 ELISA kit를 이용하여 확인하였다.After causing an inflammatory response to the Hydrangea extract of Example 1, hydrangenol of Example 2.1, and phyllodulcine of Example 2.2 with MSU (Monosodium urate) crystals, the expression level of TNF-α was measured using an ELISA kit. Confirmed.
구체적으로, 대식세포인 RAW264.7 세포는 American Type Culture Collection (ATCC, MD, USA)로부터 수득하였으며, 10% FBS 및 1% antibiotic-antimycotic가 포함된 DMEM 배지에서 5% CO2, 37℃에서 배양하였다. RAW264.7 세포를 6 웰 플레이트에 1.0 × 106 cells/ 2 ㎖/well 의 농도로 24 시간 동안 부착시킨 후 DMEM 에 1 ㎎/ml MSU(Monosodium urate) crystals와 실시예 1 및 2를 각각의 농도로 처리하여 24 시간 동안 배양하였다. 24시간 후 배양 배지를 원심 분리하여 얻어진 상층액의 TNF-α를 ELISA kit를 이용하여 정량하였다.Specifically, RAW264.7 cells, which are macrophages, were obtained from the American Type Culture Collection (ATCC, MD, USA) and cultured at 37°C in 5% CO 2 in DMEM medium containing 10% FBS and 1% antibiotic-antimycotic. did. RAW264.7 cells were attached to a 6- well plate at a concentration of 1.0 treated with and cultured for 24 hours. After 24 hours, the culture medium was centrifuged and TNF-α in the obtained supernatant was quantified using an ELISA kit.
도 15는 산수국추출물, 하이드라제놀 또는 필로둘신 처리시 MSU(Monosodium urate) crystals으로 유래된 TNF-α 발현 수치를 비교한 도이다; (a)는 산수국 추출물, (b)는 하이드라제놀, 및 (c)는 필로둘신의 농도별 처리에 따른 TNF-α 발현 수치를 나타낸다.Figure 15 is a diagram comparing the expression levels of TNF-α derived from MSU (Monosodium urate) crystals upon treatment with Hydrangea hydrangea extract, hydrazenol, or phyllodulcine; (a) shows the expression level of TNF-α according to treatment with different concentrations of Hydrangea extract, (b) hydrazenol, and (c) phyllodulcine.
그 결과 도 15 에 도시된 것과 같이. 산수국 추출물 또는 이로부터 유래하는 하이드란제놀 (Hydrangenol) 또는 필로둘신 (Phyllodulcin)은 유의적으로 TNF-α 발현을 저해하였다. 상기와 같은 결과는 산수국 추출물 또는 이로부터 유래하는 하이드란제놀(Hydrangenol), 필로둘신(Phyllodulcin) 또는 이들의 허용가능한 염을 포함하는 조성물의 경우 높은 TNF-α 발현을 저해 효과로 인해 결과적으로 고요산혈증 또는 고요산혈증 관련 대사 장애의 개선 또는 치료 효과가 있음을 의미하는 것이다.As a result, as shown in Figure 15. Hydrangea extract or hydrangenol or phyllodulcin derived from it significantly inhibited TNF-α expression. The above results are as a result of the inhibitory effect on high TNF-α expression in the case of compositions containing Hydrangea extract or hydrangenol, phyllodulcin, or acceptable salts thereof derived therefrom. This means that there is an improvement or treatment effect on metabolic disorders related to acidemia or hyperuricemia.
[제조예][Manufacturing example]
제조예 1: 정제의 제조Preparation Example 1: Preparation of tablets
상기 실시예 1의 추출물을 하기 표 5의 성분비로 혼합하고, 통상의 정제 제조방법에 따라서 타정하여 정제를 제조하였다. 제조된 정제는 모든 제형예 시험 조건에서 안정하였다.The extract of Example 1 was mixed in the ingredient ratio shown in Table 5 below, and tablets were manufactured by tableting according to a conventional tablet manufacturing method. The prepared tablets were stable under all formulation test conditions.
제조예 2: 캡슐제의 제조Preparation Example 2: Preparation of capsules
상기 실시예 1의 추출물을 하기 표 6의 성분비로 혼합하고, 젤라틴 캡슐에 충전하여 연질캡슐제를 제조하였다. 제조된 캡슐제는 모든 제형예 시험 조건에서 안정하였다.The extract of Example 1 was mixed in the ingredient ratio shown in Table 6 below and filled into a gelatin capsule to prepare a soft capsule. The prepared capsule was stable under all formulation test conditions.
제조예 3: 액제의 제조Preparation Example 3: Preparation of liquid
상기 실시예 1의 추출물을 하기 표 7의 성분비로 혼합하고, 기호에 적합한 음료 제조방법에 따라서 과병 또는 파우치에 충전하여 액제를 제조하였다. 제조된 액제는 모든 제형예 시험 조건에서 안정하였다.The extract of Example 1 was mixed at the ingredient ratio shown in Table 7 below, and filled into a fruit bottle or pouch according to a beverage preparation method suitable to taste, to prepare a liquid. The prepared liquid was stable under all formulation test conditions.
제조예 4: 젤리의 제조Preparation Example 4: Preparation of jelly
상기 실시예 1의 추출물을 하기 표 8의 성분비로 혼합하고, 기호에 적합한 젤리 제조방법에 따라서 삼면포에 충전하여 젤리를 제조하였다. 제조된 젤리는 모든 제형예 시험 조건에서 안정하였다.Jelly was prepared by mixing the extract of Example 1 in the ingredient ratio shown in Table 8 below and filling it into a three-sided cloth according to a jelly manufacturing method suitable to taste. The prepared jelly was stable under all formulation test conditions.
Claims (10)
상기 고요산혈증 관련 대사 장애는 급성 또는 만성통풍, 통풍성 발적, 통풍성 관절염, 통풍성 신결석증 및 통풍성 신병증으로 이루어진 군으로부터 선택된 어느 하나 이상의 것인, 건강기능식품 조성물.
A health functional food composition for preventing or improving hyperuricemia or hyperuricemia-related metabolic disorders, comprising Phyllodulcin or an acceptable salt thereof as an active ingredient,
A health functional food composition wherein the hyperuricemia-related metabolic disorder is at least one selected from the group consisting of acute or chronic gout, gouty flare-ups, gouty arthritis, gouty nephrolithiasis, and gouty nephropathy.
[화학식 2]
The health functional food composition according to claim 1, wherein the phyllodulcine has the structure of formula 2 below.
[Formula 2]
The health functional food composition according to claim 1, wherein the phyllodulcine or an acceptable salt thereof is derived from an extract of Hydrangea genus.
The health functional food composition according to claim 1, which inhibits xanthine oxidase.
The health functional food composition according to claim 1, wherein the health functional food has the formulation of powder, granule, tablet, capsule, pill, gel, jelly, suspension, emulsion, syrup, tea bag, leached tea, or health drink. .
상기 고요산혈증 관련 대사 장애는 급성 또는 만성통풍, 통풍성 발적, 통풍성 관절염, 통풍성 신결석증 및 통풍성 신병증으로 이루어진 군으로부터 선택된 어느 하나 이상의 것인, 약학적 조성물.
A pharmaceutical composition for the treatment or improvement of hyperuricemia or hyperuricemia-related metabolic disorders, comprising Phyllodulcin or an acceptable salt thereof as an active ingredient,
The pharmaceutical composition, wherein the hyperuricemia-related metabolic disorder is at least one selected from the group consisting of acute or chronic gout, gouty flare-ups, gouty arthritis, gouty nephrolithiasis, and gouty nephropathy.
상기 고요산혈증 관련 대사 장애는 급성 또는 만성통풍, 통풍성 발적, 통풍성 관절염, 통풍성 신결석증 및 통풍성 신병증으로 이루어진 군으로부터 선택된 어느 하나 이상의 것인, 의약외품 조성물.A quasi-drug composition for improving or preventing hyperuricemia or hyperuricemia-related metabolic disorders, comprising Phyllodulcin or an acceptable salt thereof as an active ingredient,
A quasi-drug composition, wherein the hyperuricemia-related metabolic disorder is at least one selected from the group consisting of acute or chronic gout, gouty flare-ups, gouty arthritis, gouty nephrolithiasis, and gouty nephropathy.
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| WO2020166779A1 (en) * | 2019-02-11 | 2020-08-20 | 코스맥스바이오 주식회사 | Composition for fat formation inhibition and body fat reduction, containing hydrangenol as active ingredient |
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| WO2020166779A1 (en) * | 2019-02-11 | 2020-08-20 | 코스맥스바이오 주식회사 | Composition for fat formation inhibition and body fat reduction, containing hydrangenol as active ingredient |
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