JP2005132835A - Lipid metabolism improving agent - Google Patents
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- JP2005132835A JP2005132835A JP2004295734A JP2004295734A JP2005132835A JP 2005132835 A JP2005132835 A JP 2005132835A JP 2004295734 A JP2004295734 A JP 2004295734A JP 2004295734 A JP2004295734 A JP 2004295734A JP 2005132835 A JP2005132835 A JP 2005132835A
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Abstract
Description
本発明は高脂血症をはじめとする脂質代謝異常の治療または予防に有効な生薬由来の薬剤または食品に関する。 The present invention relates to a crude drug-derived drug or food effective for the treatment or prevention of lipid metabolism abnormality including hyperlipidemia.
近年、食生活の変化により、冠動脈疾患や脳梗塞などの危険因子の一つである高脂血症は年々増加の一途をたどっている。特に血清総コレステロール濃度、血清LDL-コレステロール濃度および血清トリグリセリド濃度は、何れも冠動脈疾患の発症率と正の相関があり、それぞれ独立した危険因子であることが知られている(非特許文献1)。したがって、正常値の範囲を超えて高くなった血清総コレステロール濃度、血清LDL-コレステロール濃度および血清トリグリセリド濃度を低下させることは冠動脈疾患や脳梗塞などのリスク低減に有効と考えられる。 In recent years, due to changes in diet, hyperlipidemia, which is one of risk factors such as coronary artery disease and cerebral infarction, has been increasing year by year. In particular, serum total cholesterol concentration, serum LDL-cholesterol concentration, and serum triglyceride concentration are all positively correlated with the incidence of coronary artery disease and are known to be independent risk factors (Non-patent Document 1). . Therefore, lowering the serum total cholesterol concentration, serum LDL-cholesterol concentration, and serum triglyceride concentration that are increased beyond the normal range is considered to be effective in reducing the risk of coronary artery disease and cerebral infarction.
コレステロールは生体内では主に肝臓において合成される。すなわち、肝臓でのコレステロール合成を抑制することは血清コレステロールの低下を可能にすると考えられ、昨今は臨床においてHMG-CoA還元酵素阻害剤のようなコレステロール合成阻害薬が高コレステロール血症改善薬として広く用いられている。 Cholesterol is synthesized mainly in the liver in vivo. That is, suppressing cholesterol synthesis in the liver is thought to enable a reduction in serum cholesterol, and in recent years, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors are widely used as antihypercholesterolemia drugs in clinical practice. It is used.
また、アシルCoA:コレステロール アシルトランスフェラーゼ(ACAT)はコレステロールをエステル化する酵素であり、腸管や肝臓でのリポタンパク生成に係わる。したがってACAT活性を阻害することは血清コレステロールの低下につながると考えられ、このような薬剤の開発が日々行われている。 Acyl CoA: cholesterol acyltransferase (ACAT) is an enzyme that esterifies cholesterol and is involved in the production of lipoproteins in the intestine and liver. Therefore, inhibition of ACAT activity is thought to lead to a decrease in serum cholesterol, and such drugs are being developed every day.
これまで、高脂血症の治療にはHMG-CoA還元酵素阻害剤や胆汁酸吸着剤など様々なものが用いられている。しかしながら、高脂血症の治療には薬剤を継続して投与する必要があり、また高脂血症まで発展する前の、血清コレステロールが高めの状態であっても予防的に服用する必要もあることから、患者がより安心して服用できる天然素材の高脂血症の治療または予防剤が求められていた。 Until now, various treatments such as HMG-CoA reductase inhibitors and bile acid adsorbents have been used to treat hyperlipidemia. However, the treatment of hyperlipidemia requires continuous administration of the drug, and it is also necessary to take it prophylactically even when serum cholesterol is high before it develops to hyperlipidemia Therefore, a therapeutic or preventive agent for natural hyperlipidemia that can be taken by patients more safely has been demanded.
従来、天然素材由来の高脂血症治療剤としては、柳茶を有効成分とする技術(特許文献1)、銀杏の葉、ガジュツまたは姜黄を有効成分とする技術(特許文献2)などが知られているが未だ満足できるものではない。 Conventionally, as a therapeutic agent for hyperlipidemia derived from a natural material, a technique using Yanagi tea as an active ingredient (Patent Document 1), a technique using Ginkgo leaves, gadgets, or jade yellow as an active ingredient (Patent Document 2) are known. However, it is still not satisfactory.
ウマノスズクサ科(Aristolochiaceae)植物である細辛(Asiasarum)は、解熱、鎮痛、鎮咳、去痰、利尿などの目的で漢方処方に配合される他、鎮咳去痰薬や鼻炎用内服薬として広く一般用医薬品に用いられている。一般的に細辛といわれるものにはウスバサイシン(Asiasarum sieboldii F. MAEKAWA)、ケイリンサイシン(Asiasarum heterotropoides F. MAEKAWA var. mandshuricum F. MAEKAWA)、クロフネサイシン(Asiasarum dimidiatum F. MAEKAWA)、ウスゲサイシン(Asiasarum heterotropoides F. MAEKAWA var. seoulense F. MAEKAWA)などが知られている(非特許文献2)。 Asiasarum, a plant of the Aristolochiaceae family, is incorporated into Kampo formulas for the purpose of antipyretic, analgesic, antitussive, expectorant, diuretic, etc. It has been. Commonly said to be finely spiced are: Usasairum (Asiasarum sieboldii F. MAEKAWA), Keirinsaicin (Asiasarum heterotropoides F. MAEKAWA var. F. MAEKAWA var. Seoulense F. MAEKAWA) is known (Non-patent Document 2).
従来、細辛抽出物から得られる成分を有効成分とするフリーラジカル消去剤が開示されている(特許文献3)が、細辛抽出物の血清脂質に対する効果は報告されていない。 Conventionally, a free radical scavenger containing an ingredient obtained from a spicy extract as an active ingredient has been disclosed (Patent Document 3), but the effect of the spicy extract on serum lipids has not been reported.
本発明の目的は、安全性が高く、十分な効果を有する天然物由来の高脂血症治療剤を提供することを目的とする。 An object of the present invention is to provide a therapeutic agent for hyperlipidemia derived from a natural product having high safety and sufficient effect.
本発明者らは課題を解決するために鋭意検討した結果、生薬の細辛に優れた高脂血症の治療または予防効果があることを見出し、本発明を完成した。 As a result of intensive investigations to solve the problems, the present inventors have found that there is an effect of treating or preventing hyperlipidemia excellent in the fineness of the herbal medicine and completed the present invention.
すなわち本発明は、
(1)細辛を配合することを特徴とする脂質代謝改善剤。
(2)細辛を配合することを特徴とする高脂血症の治療または予防剤。
(3)細辛を配合することを特徴とする血清高コレステロール血症の治療または予防剤。
(4)細辛を配合することを特徴とする血清高トリグリセリド血症の治療または予防剤。
(5)細辛を配合することを特徴とするコレステロール合成阻害剤。
(6)細辛を配合することを特徴とするACAT阻害剤。
である。
That is, the present invention
(1) A lipid metabolism improving agent characterized by containing fine spicy.
(2) A therapeutic or prophylactic agent for hyperlipidemia, characterized by blending fine spicy.
(3) A therapeutic or prophylactic agent for serum hypercholesterolemia, characterized by containing fine spicy.
(4) A therapeutic or prophylactic agent for serum hypertriglyceridemia, characterized by blending fine spicy.
(5) A cholesterol synthesis inhibitor characterized by containing fine spicy.
(6) ACAT inhibitor characterized by blending fine spicy.
It is.
本発明の有効成分である細辛は、ウマノスズクサ科細辛の根または根茎を粉砕した生薬末またはエキスのことである。ここで、エキスとは生薬を水、極性溶媒、もしくはそれらの混合物などを用いて抽出したエキス、乾燥エキス、流エキスなどを含めたものである。 The fine spicy that is an active ingredient of the present invention is a herbal powder or extract obtained by pulverizing the spicy root or rhizome of the urchinaceae. Here, the extract includes a herbal medicine extracted with water, a polar solvent, or a mixture thereof, a dry extract, a flow extract, and the like.
本発明で用いる細辛は一般的に細辛とされる起源植物を用いることができるが、特にウスバサイシン(Asiasarum sieboldii F. MAEKAWA)、ケイリンサイシン(Asiasarum heterotropoides F. MAEKAWA var. mandshuricum F. MAEKAWA)が好ましい。 As for the spiciness used in the present invention, a plant that is generally considered to be spicy can be used. Is preferred.
本発明での生薬成分の投与量は患者の年齢、性別、体重、病状の程度によっても異なるが、通常、原生薬換算で大人1日あたり10 mg〜30 g程度、好ましくは大人1日あたり100mg〜3gを1〜数回に分けて投与する。 The dose of the crude drug component in the present invention varies depending on the patient's age, sex, body weight, and the degree of the disease, but is usually about 10 mg to 30 g per day for an adult drug, preferably 100 mg per day for an adult drug. Administer ~ 3g in 1 to several divided doses.
本発明の有効成分である細辛は、これまでに漢方処方や一般用医薬品として十分な使用実績があり、特に重篤な副作用も報告されていないことから極めて安全性の高い脂質低下剤、コレステロールが高めの人向けの機能性食品などになりうる。 As an active ingredient of the present invention, the spicy spice has been used enough as a traditional Chinese medicine and over-the-counter medicine, and no serious side effects have been reported. Can be a functional food for people with a high price.
本発明は、発明の効果を損なわない質的および量的範囲で、ビタミン、キサンチン誘導体、アミノ酸、賦形剤、pH調整剤、清涼化剤、懸濁化剤、消泡剤、粘稠剤、溶解補助剤、崩壊剤、結合剤、滑沢剤、抗酸化剤、コーティング剤、着色剤、矯味矯臭剤、界面活性剤、可塑剤、香料などを配合することができる。 The present invention is a qualitative and quantitative range that does not impair the effects of the invention, vitamins, xanthine derivatives, amino acids, excipients, pH adjusting agents, cooling agents, suspending agents, antifoaming agents, viscous agents, Solubilizing agents, disintegrating agents, binders, lubricants, antioxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers, fragrances and the like can be blended.
本発明の高脂血症の治療または予防剤は、細辛抽出物と必要があれば適当な添加剤を適宣加え、通常の調剤学的手法により種々の剤型、例えば散剤、顆粒剤、錠剤、カプセル剤、ドライシロップ剤、ドリンク剤、チュアブル錠、経粘膜剤などで製剤化でき、経口、非経口の投与経路で投与される。 The therapeutic or preventive agent for hyperlipidemia of the present invention is appropriately added with a spicy extract and an appropriate additive if necessary, and various dosage forms such as powders, granules, It can be formulated into tablets, capsules, dry syrups, drinks, chewable tablets, transmucosal agents, etc., and administered by oral or parenteral routes of administration.
本発明の有効成分である細辛は、血清コレステロール濃度抑制作用、血清トリグリセリド濃度上昇抑制作用、肝細胞コレステロール合成抑制作用およびACAT活性抑制作用を有することがわかった。 As a result, it was found that the spicy salt, which is an active ingredient of the present invention, has a serum cholesterol concentration inhibitory effect, a serum triglyceride concentration inhibitory effect, a hepatocyte cholesterol synthesis inhibitory effect, and an ACAT activity inhibitory effect.
以下、本発明を実施例および試験例によりさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
(細辛エキス調製)
細辛(ケイリンサイシン,Asiasarum heterotropoides F. MAEKAWA var. mandshuricum F. MAEKAWA)の根茎と根を細切した。10倍量の50%(v/v) エタノールを加え、約80℃で加熱抽出し、濾過後減圧下でエタノールを留去して、さらに濃縮を行うことにより細辛エキスを得た。
(Prepared spicy extract)
The rhizomes and roots of fine spicy (Kailinsaicin, Asiasarum heterotropoides F. MAEKAWA var. Mandshuricum F. MAEKAWA) were chopped. Ten times the amount of 50% (v / v) ethanol was added, and the mixture was extracted by heating at about 80 ° C. After filtration, the ethanol was distilled off under reduced pressure, and further concentrated to obtain a spicy extract.
(処方例1)
細辛30%エタノールエキス(乾燥エキス) 1000mg
粉糖 600mg
エロジール 36mg
アスパルテーム 9mg
低置換ヒドロキシプロピルセルロース 54mg
常法により、上記組成からなる顆粒剤を作成した。
(Formulation example 1)
Spicy 30% ethanol extract (dry extract) 1000mg
Powdered sugar 600mg
Erogil 36mg
Aspartame 9mg
Low-substituted hydroxypropylcellulose 54mg
Granules having the above composition were prepared by a conventional method.
試験例1
血清コレステロール濃度および血清トリグリセリド濃度上昇抑制作用
雄性ゴールデンシリアンハムスターを1群6匹で4群に分けた。
Test example 1
Inhibition of serum cholesterol level and serum triglyceride level increase Male golden Syrian hamsters were divided into 4 groups of 6 per group.
対照群には5%コーン油を含みコレステロールを添加していない通常食を与え、投与溶液として水10 mL/kgを1日1回2週間経口投与した。 The control group was given a normal diet containing 5% corn oil and no added cholesterol, and 10 mL / kg of water as an administration solution was orally administered once a day for 2 weeks.
残りの群には10%ココナッツ油と1%コレステロールを含む高脂肪+高コレステロール食を与え、高脂血症状態にした。そのうちの1群には投与溶液として水を、残りの群には投与溶液として細辛50%エタノールエキス10 0mg/mLまたは200mg/mL懸濁液を、それぞれ10 mL/kgで1日1回2週間経口投与した。 The remaining group was given a high fat + high cholesterol diet containing 10% coconut oil and 1% cholesterol, resulting in hyperlipidemia. One group was water as the administration solution, and the other group was 100 mg / mL or 200 mg / mL suspension of fine 50% ethanol extract as the administration solution. Orally administered for a week.
空腹時の各ハムスターの血液を採取し、血清を分離後、血清総コレステロール濃度および血清トリグリセリド濃度を測定した。血清総コレステロール濃度および血清トリグリセリド濃度の測定はそれぞれコレステロールC-IIテストワコー(和光純薬工業株式会社)およびトリグリセライドGテストワコー(和光純薬工業株式会社)を用いて行った。 The blood of each fasting hamster was collected and the serum was separated, and then the serum total cholesterol concentration and the serum triglyceride concentration were measured. Serum total cholesterol concentration and serum triglyceride concentration were measured using Cholesterol C-II Test Wako (Wako Pure Chemical Industries, Ltd.) and Triglyceride G Test Wako (Wako Pure Chemical Industries, Ltd.), respectively.
結果を、図1および図2に示した。 The results are shown in FIG. 1 and FIG.
図から明らかなように、高脂肪+高コレステロール食による血清総コレステロール濃度および血清トリグリセリド濃度の上昇が細辛50%エタノールエキス投与により有意に抑制された。 As is clear from the figure, increases in serum total cholesterol concentration and serum triglyceride concentration due to a high fat + high cholesterol diet were significantly suppressed by administration of spicy 50% ethanol extract.
試験例2 細辛エキスの肝細胞コレステロール合成抑制作用
肝細胞における細辛エキスのコレステロール合成能に対する作用を検討した。
Test Example 2 Suppression of hepatocyte cholesterol synthesis by spicy extract The effect of the spicy extract on cholesterol synthesis ability in hepatocytes was examined.
ヒト肝がん細胞株HepG2細胞をコラーゲンコートした6ウェルマルチプレート上でコンフルエントまで培養後、リポタンパクを除去した培地でさらに1日培養した。次に細辛50%エタノールエキスを500μg/mLになるように添加し、その1時間後に14C標識酢酸を0.5μCi/wellとなるように添加し、24時間インキュベートした。培養液を除去後、細胞を回収し、Folchらの方法により抽出した脂質画分をメタノールに溶解し、TLCにて展開した。コレステロールに相当するスポットの放射活性を測定し、未処置群を100%とした時の細辛50%エタノールエキス処理群のコレステロール合成能を相対値として表した。 After culturing the human hepatoma cell line HepG2 cells to confluence on a collagen-coated 6-well multiplate, the cells were further cultured in a medium from which lipoproteins were removed. Next, spicy 50% ethanol extract was added to 500 μg / mL, and after 1 hour, 14 C-labeled acetic acid was added to 0.5 μCi / well and incubated for 24 hours. After removing the culture solution, the cells were collected, and the lipid fraction extracted by the method of Folch et al. Was dissolved in methanol and developed with TLC. The radioactivity of the spot corresponding to cholesterol was measured, and the cholesterol synthesis ability of the spicy 50% ethanol extract treated group when the untreated group was taken as 100% was expressed as a relative value.
結果を表1に示した。 The results are shown in Table 1.
表から明らかなように、細辛エキス投与群では、優れたコレステロール合成阻害活性が示された。 As is clear from the table, the spicy extract administration group showed excellent cholesterol synthesis inhibitory activity.
試験例3 細辛エキスのACAT活性抑制作用
細辛エキスのACAT活性に対する作用を検討した。
Test Example 3 ACAT activity inhibitory action of spicy extract The effect of spicy extract on ACAT activity was examined.
ヒト肝がん細胞株HepG2細胞をコラーゲンコートした6ウェルマルチプレート上でコンフルエントまで培養後、リポタンパクを除去した培地でさらに1日培養した。次に細辛50%エタノールエキスを500μg/mLになるように添加し、その1時間後に14C標識オレイン酸を1μCi/wellとなるように添加し、4時間インキュベートした。培養液を除去後、細胞を回収し、Folchらの方法により得られた脂質画分をメタノールに溶解し、TLCにて展開した。コレステロールエステルに相当するスポットの放射活性を測定し、未処置群を100%とした時の細辛50%エタノールエキス処理群のACAT活性を相対値として表した。 After culturing the human hepatoma cell line HepG2 cells to confluence on a collagen-coated 6-well multiplate, the cells were further cultured in a medium from which lipoproteins were removed. Next, spicy 50% ethanol extract was added to 500 μg / mL, and after 1 hour, 14 C-labeled oleic acid was added to 1 μCi / well and incubated for 4 hours. After removing the culture solution, the cells were collected, and the lipid fraction obtained by the method of Folch et al. Was dissolved in methanol and developed with TLC. The radioactivity of the spot corresponding to cholesterol ester was measured, and the ACAT activity of the spicy 50% ethanol extract treated group when the untreated group was taken as 100% was expressed as a relative value.
HepG2細胞における細辛エキスのコレステロール合成阻害作用およびACAT活性阻害作用の結果を表1に示した。 Table 1 shows the results of the cholesterol synthesis inhibitory action and ACAT activity inhibitory action of the spicy extract in HepG2 cells.
本発明により優れた効果を有する脂質代謝改善用組成物が得られたので、医薬品、機能性食品等に有用である。 Since the composition for improving lipid metabolism having an excellent effect is obtained by the present invention, it is useful for pharmaceuticals, functional foods and the like.
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