TWI612969B - Composition of active ingredients in organic extract ofandrographispaniculata, and the use thereof in preparing hypoglycemic medicine - Google Patents
Composition of active ingredients in organic extract ofandrographispaniculata, and the use thereof in preparing hypoglycemic medicine Download PDFInfo
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Abstract
本發明係關於一種穿心蓮(Andrographis paniculata，AP)之有機溶劑萃取物，包括將穿心蓮之乾燥莖之乙醇粗萃取物以乙醇、正己烷、正丁醇與乙酸乙酯等有機溶劑進行萃取、濃縮及乾燥而得。本發明之穿心蓮有機溶劑萃取物包含具有降血糖藥理活性的成分(active ingredient, APai)，主要包含230 - 400 mg/g穿心蓮內酯（Andrographolides, A）、50 - 90 mg/g新穿心蓮內酯(Neoandrographolide, NA)及20 - 50 mg/g去氧去氫穿心蓮內酯(14-deoxy-11,12- dehydrogen-andrographolide, DDA)，可用於製備降血糖藥物。The invention relates to an organic solvent extract of Andrographis paniculata (AP), which comprises extracting and concentrating the crude ethanol extract of the dried stem of Andrographis paniculata with an organic solvent such as ethanol, n-hexane, n-butanol and ethyl acetate. Dry and get. The Andrographis paniculata organic solvent extract of the present invention comprises an active ingredient (APai) having a hypoglycemic pharmacological activity, mainly comprising 230-400 mg/g andrographolide (Andrographolides, A), 50-90 mg/g of new andrographolide. (Neoandrographolide, NA) and 20-50 mg/g dehydrogenated andrographolide (DDA), which can be used to prepare hypoglycemic drugs.
Description
本發明係關於具有降血糖功效之穿心蓮有機溶劑萃取物活性成分組成物。更特別地，本發明係關於包含具有降血糖活性成分(active ingredient, APai)之穿心蓮有機溶劑萃取物，主要包含穿心蓮內酯、新穿心蓮內酯及去氧去氫穿心蓮內酯。The present invention relates to an andrographis organic solvent extract active ingredient composition having a blood sugar lowering effect. More particularly, the present invention relates to an extract of Andrographis paniculata organic solvent comprising an active ingredient (APai) comprising mainly andrographolide, neoandrographolide and deoxyhydroandrographolide.
穿心蓮（Andrographis paniculata ）是爵床科多年生草本植物。莖細長而深綠色，稜角處有縱溝和翼膜。莖的橫截面四方形。葉是披針形，無毛。中國、印度、東南亞和臺灣等地有廣泛栽培。氣輕微、味道極苦且持久。在馬來西亞，穿心蓮被稱為「Hempedu Bumi」，即是“地球膽汁”之意，也是傳統醫藥中味道最苦的植物之一。在中醫藥的五行學說中認為苦入心，而穿心蓮只要你含入一小片它的葉子，馬上可以感受到，那種刻骨銘心的苦，像是直入你的心中，故名『穿心蓮』。 Andrographis paniculata is a perennial herb of the genus. The stem is slender and dark green with longitudinal grooves and wing membranes at the corners. The stem has a square cross section. The leaves are lanceolate and glabrous. China, India, Southeast Asia and Taiwan are widely cultivated. It is mild, very bitter and long lasting. In Malaysia, Andrographis paniculata is called “Hempedu Bumi”, which means “earth bile” and one of the most bitter plants in traditional medicine. In the five elements of Chinese medicine, I think that bitterness comes into my heart, and if you wear a small piece of its leaves, you can feel it immediately. The kind of unforgettable bitterness seems to go straight into your heart, hence the name "through the heart."
穿心蓮的藥用部位是乾燥莖與葉子，穿心蓮葉含二萜內酯化合物：去氧穿心蓮內酯(Deoxyandrographolide) 0．1 ％以上，穿心蓮內酯(Andrographolide) l.5％以上，新穿心蓮內酯(Neoandrographolide) 0．2％以上，及高穿心蓮內酯(Homoandrographolide)，潘尼內酯 (Panicolide)。還含有穿心蓮烷(Andrographan)，穿心蓮酮(Andrographon)，穿心蓮甾醇（Andrographosterin)，β-谷甾醇-D-葡萄糖甙等。根部除了含有穿心蓮內酯之外，還含有5-羥基-7， 8，2"，3"-四甲氧基黃酮(Mono-o-methylwithtin)、5-羥基-7，8，2"-三甲氧基黃酮 (Andrographin)、5，2"-二羥基-7，8-二甲氧基黃酮(Panicolin)、芹菜素-7，4"-二甲醚 (Apigenin-7，4"-dimethyl ether)、a1-谷甾醇和 KH2 PO4 等。全草尚含 l4-去氧-11-氧化穿心蓮內酯醋(14-Deoxy-ll-oxoandrographolide)、14-去氧-11，12-二去氫穿心蓮內酯 (14-Deoxy-ll，12-didehydroandrographolide)。另據初步分析，還含有甾醇皂甙、糖類及縮合鞣質等酚類物質。又從葉、嫩枝、胚軸、根部和胚芽所得的癒合組織，經培養分離，可得到三種倍半萜內酯化合物：欖核蓮內酯A、B和C (Pa－niculides A、B、C)。The medicinal part of Andrographis paniculata is dry stems and leaves, and the penicillin leaves contain diterpene lactone compounds: Deoxyandrographolide 0.1% or more, Andrographolide (1.5%), New andrographolide (Neoandrographolide) 0.2% or more, and high andrographolide (Homoandrographolide), panicolide (Panicolide). It also contains Andrographan, Andrographon, Andrographosterin, β-sitosterol-D-glucoside and the like. In addition to the andrographolide, the root also contains 5-hydroxy-7,8,2",3"-tetramethoxylated flavonoids (Mono-o-methylwithtin), 5-hydroxy-7,8,2"-trimethyl Andrographin, 5,2"-dihydroxy-7,8-dimethoxyflavone (Panicolin), apigenin-7,4"-dimethyl ether (Apigenin-7,4"-dimethyl ether) , a1-sitosterol and KH 2 PO 4 and the like. Whole grass still contains l4-deoxy-ll-oxoandrographolide, 14-deoxy-11,12-didehydroandrographolide (14-Deoxy-ll,12- Didehydroandrographolide). According to preliminary analysis, it also contains phenolic substances such as sterol saponins, sugars and condensed tannins. The healing tissues obtained from leaves, shoots, hypocotyls, roots and germs can be isolated and cultured to obtain three sesquiterpene lactone compounds: lanolinide A, B and C (Pa-niculides A, B, C).
穿心蓮水萃取物(APHE )及穿心蓮內酯（Andrographolides, A）已被發表具有降血糖、降血脂、抗菌、抗發炎及抗癌等功能。其中穿心蓮內酯已知具有祛熱解毒，消炎止痛的功效，對細菌性、病毒性上呼吸道感染(急、慢性扁桃腺炎及咽喉腫痛)及細菌性痢疾、胃腸炎有特殊療效(Md. Sanower Hossain等人，The Scientific World Journal 2014:1-28, 2014)。中華民國專利I355933已描述一種作為腫瘤壞死因子（TNF-α）拮抗劑之穿心蓮內酯及其藥學組成物。另外，已有利用穿心蓮內酯作為活性成分，製作一以治癒傷口及/或美白皮膚的醫藥組合物(中華民國專利201524532)。Andrographis water extract (AP HE ) and andrographolide (Andrographolides, A) have been published to have functions of lowering blood sugar, lowering blood fat, antibacterial, anti-inflammatory and anti-cancer. Among them, andrographolide is known to have antipyretic, anti-inflammatory and analgesic effects, and has special effects on bacterial, viral upper respiratory tract infections (urgent, chronic tonsillitis and sore throat) and bacterial dysentery and gastroenteritis (Md. Sanower Hossain et al., The Scientific World Journal 2014: 1-28, 2014). The Republic of China Patent No. I355933 has described an andrographolide which is a tumor necrosis factor (TNF-α) antagonist and a pharmaceutical composition thereof. Further, a pharmaceutical composition for healing wounds and/or whitening skin has been prepared by using andrographolide as an active ingredient (Republic of China Patent 201524532).
糖尿病(Diabetes mellitus, DM) 為一種人體將葡萄糖（糖類）轉換成能量的方式出現變化的疾病，其特徵在於伴隨著脂肪和蛋白質代謝紊亂的高血糖症。微血管和糖尿病的大血管並發症包括心血管疾病，失明，腎功能衰竭和外週神經損傷，是發病率和死亡的主要原因[H.T. Li, XD WU, AK Daveyet al ., 2011.]。Diabetes mellitus (DM) is a disease in which the body changes its metabolism of glucose (sugar) into energy, characterized by hyperglycemia accompanied by disorders of fat and protein metabolism. Macrovascular complications of microvascular and diabetic diseases including cardiovascular disease, blindness, renal failure and peripheral nerve injury are the main causes of morbidity and mortality [HT Li, XD WU, AK Davey et al ., 2011.].
糖尿病有兩類，包括第I型糖尿病（胰島素依賴型糖尿病, IDDM) 及第II型糖尿病（非-胰島素依賴型糖尿病, NIDDM)。第II型糖尿病特徵在於周邊胰島素抗性及胰島素的分泌不足[S.E. Kahn, 2003 ]。通常，該疾病的出現是由於β細胞之胰島素分泌漸進性失能，以克服對該激素的敏感性降低[SE Kahn, 2001; M. Prentki 與 C.J. Nolan, 2006.]。此會導致高血糖症，而可能反過來又對β細胞產生有害作用[R.P. Robertson, 2004]。.There are two types of diabetes, including type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Type II diabetes is characterized by peripheral insulin resistance and insufficient insulin secretion [S.E. Kahn, 2003]. Typically, the disease occurs due to the progressive disability of insulin secretion from beta cells to overcome the reduced sensitivity of the hormone [SE Kahn, 2001; M. Prentki and C.J. Nolan, 2006.]. This can lead to hyperglycemia, which in turn can have a detrimental effect on beta cells [R.P. Robertson, 2004]. .
雖然已有文獻報導，在大白鼠實驗中，穿心蓮內酯(andrographolide)可以降低血糖濃度，並在胰島素缺乏時提高對血糖的利用率(Yu BC等人, Planta Med. 69(12):1075-9, 2003；Zhang XF, Tan BK., Clin Exp Pharmacol Physiol. 27(5-6):358-63, 2000)。然而，尚未有關於穿心蓮有機溶劑萃取物中具有降血糖功效之活性組合物已被發表。Although it has been reported in the literature, andrographolide can lower blood glucose levels in rats and improve blood glucose utilization in the absence of insulin (Yu BC et al, Planta Med. 69(12):1075- 9, 2003; Zhang XF, Tan BK., Clin Exp Pharmacol Physiol. 27(5-6): 358-63, 2000). However, an active composition having an antihyperglycemic effect on the extract of Andrographis paniculata organic solvent has not been published.
而本發明係以穿心蓮乾燥莖中所含之具有降血糖活性的有機溶劑萃取物為目標，分析其中的指標化合物：穿心蓮內酯（Andrographolides, A）、新穿心蓮內酯(Neoandrographolide, NA)、及去氧去氫穿心蓮內酯(14-deoxy-11,12- dehydrogen-andrographolide , DDA)之含量，進而完成本發明包含具有降血糖藥理活性的成分(active ingredient, APai)之穿心蓮有機溶劑萃取物。The present invention aims to analyze the indicator compound: andrographolides (A), Neoandrographolide (NA), and the organic solvent extract containing the hypoglycemic activity contained in the dried stem of Andrographis paniculata. The content of 14-deoxy-11,12-dehydrogen-andrographolide (DDA) is deoxygenated to complete the amarylocyte organic solvent extract containing the active ingredient (APai) of the present invention.
於是，本發明之一方面係關於，一種包含降血糖藥理活性成分(active ingredient, APai)之穿心蓮有機溶劑萃取物，主要包含230 - 400 mg/g穿心蓮內酯（Andrographolides, A）、50 - 90 mg/g新穿心蓮內酯(Neoandrographolide, NA)及20 - 50 mg/g去氧去氫穿心蓮內酯(14-deoxy-11,12- dehydrogen-andrographolide , DDA)。於本發明之一較佳具體實施態樣，所述之穿心蓮有機溶劑萃取物主要包含180 - 380 mg/g穿心蓮內酯、40 - 85 mg/g新穿心蓮內酯及16 - 45 mg/g去氧去氫穿心蓮內酯。Accordingly, one aspect of the present invention relates to an andrographis organic solvent extract comprising a hypoglycemic active ingredient (APai), comprising mainly 230-400 mg/g andrographolide (A), 50-90 Mg/g Neoandrographolide (NA) and 20-50 mg/g dehydrogenated andrographolide (DDA). In a preferred embodiment of the present invention, the extract of Andrographis paniculata organic solvent mainly comprises 180 - 380 mg / g andrographolide, 40 - 85 mg / g of new andrographolide and 16 - 45 mg / g Oxygen dehydroandrographolide.
於本發明之一些具體實施態樣，所述之穿心蓮有機溶劑萃取物包含80-99%之活性成分(APai)。於本發明之一項具體實施態樣，所述之穿心蓮有機溶劑萃取物包含95-99%之活性成分(APai)。In some embodiments of the invention, the Andrographis paniculata organic solvent extract comprises 80-99% active ingredient (APai). In a specific embodiment of the present invention, the Andrographis paniculata organic solvent extract comprises 95-99% active ingredient (APai).
於本發明之一些具體實施態樣，所述之穿心蓮有機溶劑萃取物活性成分(APai)包含230 - 450 mg/g穿心蓮內酯（Andrographolides, A）、50 - 90 mg/g新穿心蓮內酯(Neoandrographolide, NA)及20 - 60 mg/g去氧去氫穿心蓮內酯(14-deoxy-11,12- dehydrogen-andrographolide , DDA)。於本發明之一項較佳具體實施態樣，所述之穿心蓮有機溶劑萃取物活性成分(APai)包含230 - 280 mg/g穿心蓮內酯、50 - 70 mg/g新穿心蓮內酯及20 - 40 mg/g去氧去氫穿心蓮內酯。In some embodiments of the present invention, the Andrographis paniculata organic solvent extract active ingredient (APai) comprises 230-450 mg/g andrographolide (Andrographolides, A), 50-90 mg/g of new andrographolide ( Neoandrographolide, NA) and 20-60 mg/g dehydrogenated androgenolactone (14-deoxy-11,12-dehydrogen-andrographolide, DDA). In a preferred embodiment of the present invention, the andrographolide organic solvent extract active ingredient (APai) comprises 230-280 mg/g andrographolide, 50-70 mg/g of new andrographolide, and 20- 40 mg/g deoxygenated dehydroandrographolide.
於本發明之一些具體實施態樣，所述之穿心蓮有機溶劑萃取物包含99-100%穿心蓮有機溶劑萃取物活性成分(APai)，其中所述之活性成分(APai)包含25%-40%穿心蓮內酯、5%-9%新穿心蓮內酯及2%-5%去氧去氫穿心蓮內酯。於本發明之一項具體實施態樣，所述之穿心蓮有機溶劑萃取物包含25-30%穿心蓮內酯、6-8%新穿心蓮內酯及3-4%去氧去氫穿心蓮內酯。In some embodiments of the present invention, the Andrographis paniculata organic solvent extract comprises 99-100% Andrographis paniculata organic solvent extract active ingredient (APai), wherein the active ingredient (APai) comprises 25%-40% Andrographis paniculata Lactone, 5%-9% new andrographolide and 2%-5% deoxygenated andrographolide. In a specific embodiment of the present invention, the Andrographis paniculata organic solvent extract comprises 25-30% andrographolide, 6-8% new andrographolide, and 3-4% deoxyhydroandrographolide.
本發明之另一方面，係關於一種具有降血糖藥理活性之組成物，包含所述之穿心蓮有機溶劑萃取物，其特徵在於包含23%-40%穿心蓮內酯、5%-9%新穿心蓮內酯及2%-5%去氧去氫穿心蓮內酯。Another aspect of the invention relates to a composition having hypoglycemic pharmacological activity, comprising the extract of Andrographis paniculata organic solvent, characterized by comprising 23%-40% andrographolide, 5%-9% of new andrographolide Ester and 2%-5% deoxygenated dehydroandrographolide.
於本發明之一些具體實施態樣，所述之組成物為一醫藥組成物。於本發明之其他具體實施態樣，所述之所述之組成物為一保健食品組成物。In some embodiments of the invention, the composition is a pharmaceutical composition. In other specific embodiments of the invention, the composition is a health food composition.
本發明之另一方面，係關於一種用於調控糖尿病患者血糖之醫藥組成物，包含所述之穿心蓮有機溶劑萃取物及醫藥上可接受的載體、稀釋劑或賦形劑。Another aspect of the invention relates to a pharmaceutical composition for regulating blood glucose in a diabetic patient, comprising the extract of Andrographis paniculata organic solvent and a pharmaceutically acceptable carrier, diluent or excipient.
於本說明書中所稱的“穿心蓮有機溶劑萃取物”係指，穿心蓮乾燥莖之乙醇粗萃取物進一步以乙醇、正己烷、正丁醇與乙酸乙酯等有機溶劑進行萃取、濃縮及乾燥而得者。經由活性測試及分析，本發明之穿心蓮有機溶劑萃取物包含具有降血糖活性成分(active ingredient, APai)。The "andrographis organic solvent extract" as referred to in the present specification means that the crude ethanol extract of the dried stem of Andrographis paniculata is further extracted, concentrated and dried by an organic solvent such as ethanol, n-hexane, n-butanol or ethyl acetate. By. Through the activity test and analysis, the Andrographis paniculata organic solvent extract of the present invention comprises an active ingredient (APai).
本發明之其他特色及優點將於下列實施範例中被進一步舉例與說明，而該實施範例僅作為輔助說明，並非用於限制本發明之範圍。The other features and advantages of the present invention are further exemplified and illustrated in the following examples, which are intended to be illustrative only and not to limit the scope of the invention.
實施例一、Embodiment 1 穿心蓮有機溶劑萃取物之製備Preparation of andrographis organic solvent extract
將穿心蓮乾燥莖(4.0 kg)切碎，並於迴流下以60升乙醇萃取兩次。將組合之萃取物於減壓下進行濃縮，而得到乾燥的粗萃取物(產率8.75%)。將前述之乙醇粗萃取物依序使用下列有機溶劑及萃取條件：乙醇(95%)在室溫下萃取36-72小時共5-7次、正己烷(100%)在室溫下萃取12-36小時共4-7次、正丁醇(100%)在室溫下萃取12-48小時共7-10次、乙酸乙酯(100%)在室溫下萃取12-36小時共7-10次，透過系統分離法進行連續萃取與分離，之後將所得之有機萃取物利用減壓濃縮機及烘箱進行濃縮與乾燥，取得萃取物粉末，即本發明之穿心蓮有機溶劑萃取物活性成分(APai)。The dried stem of Andrographis paniculata (4.0 kg) was chopped and extracted twice with 60 liters of ethanol under reflux. The combined extracts were concentrated under reduced pressure to give a dried crude extract (yield: 8.75%). The foregoing crude ethanol extract is sequentially subjected to the following organic solvents and extraction conditions: ethanol (95%) is extracted at room temperature for 36-72 hours for 5-7 times, and n-hexane (100%) is extracted at room temperature for 12- 4-7 times in 36 hours, n-butanol (100%) was extracted at room temperature for 12-48 hours for 7-10 times, and ethyl acetate (100%) was extracted at room temperature for 12-36 hours for a total of 7-10 Then, continuous extraction and separation are carried out by a system separation method, and then the obtained organic extract is concentrated and dried by a vacuum concentrator and an oven to obtain an extract powder, that is, the active ingredient of the organic solvent extract of the present invention (APai) .
實施例二、Embodiment 2 穿心蓮有機溶劑萃取物之活性成分(active ingredient, APai)組成物的指標化合物含量分析Analysis of the content of index compounds in the composition of active ingredient (APai) of Andrographis paniculata extract
進一步利用二溶劑-HPLC分析系統，測定本發明穿心蓮有機溶劑萃取物活性成分組成物(APai)之主要組成物質的含量，溶劑A為100%乙腈，溶劑B為0.25%甲酸，分析條件如下述： 1. 移動相(Mobil phase) 起始條件為31%溶劑B，0-12分鐘改變成35%溶劑B，12-23分鐘改變成35%溶劑B，23-28分鐘改變成31%溶劑B，28-38分鐘改變成31%溶劑B。使用Shimadzu Class VPTM 軟體進行整合與校正。透過高峰面積與線性回歸進行評估。 2. 管柱：LiChrospher® C18, 5 μm, (250 X 4.6 mm, 5 mm) 3. 流速：1 mL / min 4. UV偵測：210, 232 and 254 nm，使用SPD-M10AVP photodiode array detector (Japan) 5. 注射體積：20 μLFurther, the content of the main constituent substance of the active ingredient composition (APai) of the organic solvent extract of the present invention is determined by a two-solvent-HPLC analysis system, the solvent A is 100% acetonitrile, and the solvent B is 0.25% formic acid, and the analysis conditions are as follows: 1. Mobil phase Starting conditions are 31% solvent B, 0-12 minutes changed to 35% solvent B, 12-23 minutes changed to 35% solvent B, 23-28 minutes changed to 31% solvent B, Change to 31% solvent B at 28-38 minutes. Using Shimadzu Class VP TM software integration correction. Evaluate through peak area and linear regression. 2. Column: LiChrospher ® C18, 5 μm, (250 X 4.6 mm, 5 mm) 3. Flow rate: 1 mL / min 4. UV detection: 210, 232 and 254 nm, using SPD-M10AVP photodiode array detector ( Japan) 5. Injection volume: 20 μL
接著進行檢量線的製作，定量活性成分組合物中A, NA及DDA之含量。藉由配置標準物工作溶液(10 - 300 µg/mL)及內在標準物工作溶液，來訂出檢量曲線(Calibration curve)數據。透過繪製標準物對內在標準物之高峰面積比例圖，來建構檢量曲線。準確度以日內(intra-day)及日間(inter-day) RSD表示。標準物之日內及日間RSD是分別於同一天及連續三天進行分析得到，每次實驗包含三重複組。檢出極限(LOD)係測定為對應於信號對雜訊比為3:1之標準物含量。定量極限(LOQ)係測定為能夠以可接受之精確度及正確度，在具有信號對雜訊比為至少10之實驗條件下得到的最低標準物濃度。Next, the preparation of the calibration curve is performed to quantify the contents of A, NA and DDA in the active ingredient composition. Calibration curve data was prepared by configuring a standard working solution (10 - 300 μg/mL) and an internal standard working solution. The calibration curve is constructed by plotting the standard against the peak area ratio of the intrinsic standard. Accuracy is expressed in intra-day and inter-day RSD. The intra- and inter-day RSD of the standard was obtained on the same day and three consecutive days, and each experiment contained three replicates. The limit of detection (LOD) was determined to correspond to a standard to the signal to noise ratio of 3:1. The limit of quantitation (LOQ) is determined as the minimum standard concentration that can be obtained with acceptable accuracy and accuracy under experimental conditions with a signal to noise ratio of at least 10.
圖1所示為混合標準物溶液於210、232及254 nm下測得之重疊層析圖譜。A、NA及DDA標準物之滯留時間(retention time)分別為6.13、11.83及18.68 min，而卡巴氮平(內在標準物)之滯留時間為10.03 mA、NA及DDA標準物係於232、210及210 nm呈現最大吸光值。因此，A標準物的線性度、精確度及回收率係於232 nm下進行計算；而NA及DDA標準物的線性度、精確度及回收率係於210 nm下進行計算。此等選擇的吸光值亦應用於卡巴氮平(內在標準物)之吸光值。Figure 1 shows the overlapping chromatograms of the mixed standard solutions at 210, 232 and 254 nm. The retention times of A, NA and DDA standards were 6.13, 11.83 and 18.68 min, respectively, while the retention time of carbazapine (intrinsic standard) was 10.03 mA, NA and DDA standards were at 232, 210 and The maximum absorbance at 210 nm. Therefore, the linearity, accuracy, and recovery of the A standard were calculated at 232 nm; the linearity, accuracy, and recovery of the NA and DDA standards were calculated at 210 nm. The absorbance values of these choices are also applied to the absorbance of kabazapine (intrinsic standard).
經由注射八種濃度(10 - 300 µg/20 µL)之含有A、NA及DDA的標準物工作溶液，來評估標準曲線之線性度。將高峰面積與濃度進行最小平方線性回歸分析，以計算校準方程式和相關判定係數。單獨A標準物於濃度範圍20 - 300 µg/20 µL內獲得的線性度為0.9990 ± 0.0003，或者以A標準物對內在標準物之鋒面積比與相關判定係數獲得的線性度為0.9948 ± 0.0009。單獨NA 標準物於濃度範圍20 - 300 µg/20 µL內獲得的線性度為0.9986 ± 0.0002，或者以NA標準物對內在標準物之鋒面積比與相關判定係數獲得的線性度為0.9939 ± 0.0012。單獨DDA標準物於濃度範圍20 - 300 µg/20 µL內獲得的線性度為0.9956 ± 0.0020，或者以DDA標準物對內在標準物之鋒面積比與相關判定係數獲得的線性度為0.9988 ± 0.0004。The linearity of the standard curve was evaluated by injecting eight concentrations (10 - 300 μg / 20 μL) of the standard working solution containing A, NA and DDA. A least squares linear regression analysis was performed on the peak area and concentration to calculate the calibration equation and the associated decision coefficients. The linearity of the A standard alone in the concentration range of 20 - 300 μg / 20 μL was 0.9990 ± 0.0003, or the linearity obtained by the A standard against the intrinsic standard front area ratio and the correlation coefficient was 0.9948 ± 0.0009. The linearity of the NA standard alone in the concentration range of 20 - 300 μg / 20 μL was 0.9986 ± 0.0002, or the linearity of the NA standard to the intrinsic standard front area ratio and the correlation coefficient was 0.9939 ± 0.0012. The linearity of the DDA standard obtained in the concentration range of 20 - 300 μg / 20 μL was 0.9956 ± 0.0020, or the linearity obtained by the DDA standard against the intrinsic standard front area ratio and the correlation coefficient was 0.9988 ± 0.0004.
中間精確度可呈現出實驗室偏差，以日內及日間偏差表示。於同一天(日內)及於不同天(日間)進行A、NA及DDA標準物之八種濃度(10 - 300 μg/20 μL)判定，並以相對標準偏差百分比(% RSD)或變異係數表示(CV)。結果顯示，對於A標準物之日內及日間分析的% RSD係落在0.54 - 9.21範圍內；對於NA標準物之日內及日間分析的% RSD係落在0.54 - 8.03範圍內；而對於DDA標準物之日內及日間分析的% RSD係落在1.00 - 14.97範圍內。Intermediate accuracy can present laboratory deviations expressed as intraday and interday deviations. Eight concentrations of A, NA and DDA standards (10 - 300 μg/20 μL) were determined on the same day (intraday) and on different days (daytime) and expressed as percent relative standard deviation (% RSD) or coefficient of variation. (CV). The results show that the % RSD for the intra- and inter-day analysis of the A standard falls within the range of 0.54 - 9.21; the % RSD for the intra- and inter-day analysis of the NA standard falls within the range of 0.54 - 8.03; The % RSD analyzed during the day and during the day falls within the range of 1.00 - 14.97.
該方法的準確性是從回收率研究確定。預分析樣品中摻入了三種不同濃度的A、NA及DDA標準物，然後將混合物以建議的方法進行分析。結果得知，A標準物之回收率範圍介於96.93 - 100.23%，而計算A標準物之平均回收百分比值為98.41 ± 1.68%。NA標準物之回收率範圍介於97.03 - 102.14%，而計算NA標準物之平均回收百分比值為99.64 ± 2.55%。DDA標準物之回收率範圍介於97.09 - 105.23%，而計算DDA標準物之平均回收百分比值為100.92 ± 4.40%。The accuracy of the method was determined from the recovery study. The pre-analytical samples were spiked with three different concentrations of A, NA and DDA standards and the mixture was analyzed in the recommended manner. As a result, the recovery rate of the A standard ranged from 96.93 to 100.23%, and the average recovery percentage of the calculated A standard was 98.41 ± 1.68%. The recovery of NA standards ranged from 97.03 to 102.14%, while the average recovery percentage of calculated NA standards was 99.64 ± 2.55%. The recovery of DDA standards ranged from 97.09 to 105.23%, while the average recovery percentage of DDA standards was calculated to be 100.92 ± 4.40%.
藉由比對由光二極體列陣偵測儀得到之標準物與樣本的高峰光譜及純度，確定相對應於存在APai中之A、NA與DDA的高峰。圖1顯示本發明穿心蓮有機溶劑萃取物活性組成於210、232及254 nm下的HPLC多重層析圖譜。存在APai中A、NA 及DDA之含量計算結果如下表1所示。 因此，穿心蓮內酯(A)含量為235.10±1.64 mg/g；新穿心蓮內酯(NA)含量為52.31±4.62 mg/g；去氧去氫穿心蓮內酯(DDA)含量為22.68±1.13 mg/g。本實例提供之分析數值，會因所採收之穿心蓮來源、產地及產季而有所變化，但經由以下的藥理活性實驗證明，本發明萃取方法所得之穿心蓮有機溶劑萃取物活性成分具有降血糖功效。表 1. 存在APai中A、NA 及DDA之含量 
實施例三、Embodiment 3 穿心蓮有機溶劑萃取物活性成分組成物對於Andrographis organic solvent extract active ingredient composition for 鏈佐黴素STZ-誘導之第II型Streptozotocin STZ-induced type II 糖尿病鼠之血糖調控功效評估Evaluation of blood glucose regulation efficacy in diabetic rats
雄性ICR小鼠(19-21 g)係購自台灣BioLASCO Co., Ltd。小鼠餵養於環球科技大學之動物中心，溫度調控於22 ± 2℃，相對濕度55 ± 5%且於實驗前一周施予12小時光照/12小時黑暗週期。對於第II型糖尿病鼠之誘導，係將菸鹼醯胺(Sigma, Saint Louis, MO, USA)食鹽水溶液(210 mg/kg b.w.)以腹膜內注射入小鼠，經15分鐘後將於使用前溶解於檸檬酸鹽緩衝液(pH 4.5)之鏈佐黴素(STZ) (Sigma, 180 mg/kg b. w., i.p.注射)投藥給該小鼠。對照組係接受該二種載劑者。於實驗期間，每週一次記錄實驗動物之食物攝取量及體重。本發明穿心蓮有機溶劑萃取物活性成分組成物APai之投藥量為：E10組: APai 10 mg/kg ; E20組: APai 20 mg/kg ; E40組: APai 40 mg/kg ; E80組: APai 80 mg/kg。其中為如前述實施例一所製備得之穿心蓮有機溶劑萃取物活性成分組成物，經Tween 20溶解後調整成0.5%甲基纖維素(CMC)溶液。臨床觀察 Male ICR mice (19-21 g) were purchased from BioLASCO Co., Ltd., Taiwan. Mice were fed an animal center at the University of Science and Technology of the United States, with a temperature regulation of 22 ± 2 ° C, a relative humidity of 55 ± 5% and a 12-hour light/12-hour dark cycle one week prior to the experiment. For the induction of type II diabetic rats, nicotinic acid amide (Sigma, Saint Louis, MO, USA) aqueous saline solution (210 mg/kg bw) was intraperitoneally injected into mice, and 15 minutes later, before use. The mice were administered to streptomycin (STZ) (Sigma, 180 mg/kg bw, ip injection) dissolved in citrate buffer (pH 4.5). The control group received the two carriers. The food intake and body weight of the experimental animals were recorded once a week during the experiment. The dosage of APai administered by the active ingredient of Andrographis paniculata organic solvent extract is: E10 group: APai 10 mg/kg; E20 group: APai 20 mg/kg; E40 group: APai 40 mg/kg; E80 group: APai 80 mg /kg. Among them, the active ingredient composition of Andrographis paniculata organic solvent extract prepared as in the above Example 1 was dissolved in Tween 20 and adjusted to a 0.5% methylcellulose (CMC) solution. Clinical Observation
每天至少進行兩次觀察動物之身體狀況，每次觀察的時間間隔不少於6小時，以確定動物的健康或死亡狀態。每天至少一次觀察試驗動物之臨床病徵，記錄試驗動物所表現出的毒性作用，包括該等毒性作用的開始時間及過程。試驗結束後，將存活的小鼠犧牲；之後進行屍體解剖，採取血液樣本進行血清生化分析。Observe the physical condition of the animal at least twice a day, with an interval of not less than 6 hours per observation to determine the health or death of the animal. The clinical signs of the test animals were observed at least once a day, and the toxic effects exhibited by the test animals were recorded, including the start time and course of the toxic effects. At the end of the experiment, the surviving mice were sacrificed; then autopsy was performed and blood samples were taken for serum biochemical analysis.
由臨床觀察之結果顯示，本發明之穿心蓮有機溶劑萃取物活性成分組成物APai (E10、E20、E40、E80 mg/kg)可降低因菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠的飲水量(圖2A)。且APai (E10、E20、E40、E80 mg/kg)能夠降低因菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠的飲食量(圖2B)。表示本發明之可減輕糖尿病小鼠的臨床病徵。口服葡萄糖耐受性試驗 ( OGTT) As a result of clinical observation, the active ingredient composition of the Andrographis paniculata organic solvent extract of the present invention APai (E10, E20, E40, E80 mg/kg) can reduce the type II diabetes induced by nicotinamide-chain-mycin The amount of water consumed by the rats (Fig. 2A). And APai (E10, E20, E40, E80 mg/kg) was able to reduce the dietary intake of type II diabetic mice induced by nicotinamide-streptomycin (Fig. 2B). It is indicated that the present invention can alleviate the clinical signs of diabetic mice. Oral glucose tolerance test (OGTT)
進行口服葡萄糖耐受性試驗，來評估周邊葡萄糖利用率。將糖尿病小鼠斷食16小時，同時記錄體重。在投藥本發明之穿心蓮有機溶劑萃取物活性成分組成物APai (E10、E20、E40、E80 mg/kg) 30分鐘後，於給予葡萄糖之前採集血液樣本測定樣本中的血糖濃度，此為0 min血糖值。給予葡萄糖(2 g/kg) 30、60、90及120分鐘後，採集血液樣本測定樣本中的血糖濃度。An oral glucose tolerance test was performed to assess peripheral glucose utilization. Diabetic mice were fasted for 16 hours while recording body weight. After administering the active ingredient composition APai (E10, E20, E40, E80 mg/kg) of the Andrographis paniculata extract in the present invention for 30 minutes, a blood sample is collected before the glucose is administered to determine the blood glucose concentration in the sample, which is 0 min blood glucose. value. After administration of glucose (2 g/kg) for 30, 60, 90 and 120 minutes, a blood sample was taken to determine the blood glucose concentration in the sample.
圖3之結果顯示，給予STZ會明顯提升處理組小鼠之血糖值，與正常小鼠(Sham)組比較，在0.5、1、1.5及2小時有顯著的差異。The results in Figure 3 show that administration of STZ significantly increased the blood glucose level of the treated mice, with significant differences at 0.5, 1, 1.5, and 2 hours compared to the normal (Sham) group.
APai可改善STZ的傷害作用，尤其在1.5及2小時的血糖有顯著的差異，隨著APai劑量的升高(10、20、40 mg/kg)，降低血糖的效果越益明顯，但升高劑量的80 mg/kg時，效果變差。APai can improve the damage of STZ, especially in 1.5 and 2 hours of blood glucose. With the increase of APai dose (10, 20, 40 mg / kg), the effect of lowering blood sugar is more obvious, but increased. At a dose of 80 mg/kg, the effect is worse.
而圖4之血糖監測結果顯示，給予STZ明顯升高空腹血糖，與Sham比較時，在0, 7, 14, 21 及28天的血糖值有顯著的差異。APai (E20、E40、E80 mg/kg)可降低菸鹼醯胺-鏈佐黴素所誘導第II型糖尿病小鼠血液血糖值升高現象，其中以E40 mg/kg連續投藥28天的效果最佳。糖化血色素(HbA1c) 分析 The blood glucose monitoring results in Figure 4 showed that STZ was significantly increased in fasting blood glucose. When compared with Sham, there was a significant difference in blood glucose values at 0, 7, 14, 21 and 28 days. APai (E20, E40, E80 mg/kg) can reduce the blood glucose level of type II diabetic mice induced by nicotinamide-streptavidin, and the effect of continuous administration of E40 mg/kg for 28 days is the most effective. good. Glycated hemoglobin (HbA1c) analysis
「糖化血色素」(HbA1c)是指人體血液中的紅血球含有血色素，當血液中的葡萄糖進入紅血球，和血紅素結合後，就形成糖化血色素。一般紅血球平均壽命為120天，葡萄糖附在血色素上不容易脫落，因此檢查血中糖化血色素的濃度，可以反應體內最近2-3個月的血糖控制情況。HbA1C 與血糖的最大差別在於血糖值只代表抽血當時的血糖狀態，而較長時期的血糖控制情形，則須靠 HbA1C 來反映。HbA1C 是偵測早期糖尿病的優良指標，這些患者的病情較輕，原本稍微偏高的血糖在飢餓一段時間後常掉回正常範圍，因此空腹測定血糖時，經常遺漏這類患者，然而 HbA1C 卻無此缺點2009年美國糖尿病學會提出以「糖化血色素」＞=6.5%作為糖尿病診斷標準，因此「糖化血色素」除了當作糖尿病的血糖追蹤指標以外，也是新的診斷工具。HbA1C (醣化血色素，glycated hemoglobin) 近幾年已被廣泛應用於需要監控血糖值的糖尿病患者，它可反應採血前一個月左右的血糖控制狀況，並可用來監督血糖控制的情形，還可作為調整藥量的依據。"Glycated hemoglobin" (HbA1c) means that red blood cells in human blood contain hemoglobin. When glucose in the blood enters red blood cells and combines with hemoglobin, glycated hemoglobin is formed. The average life span of red blood cells is 120 days. Glucose is not easy to fall off on hemoglobin. Therefore, checking the concentration of glycated hemoglobin in blood can reflect the blood sugar control in the last 2-3 months. The biggest difference between HbA1C and blood sugar is that the blood sugar level only represents the blood sugar status at the time of blood draw, and the longer-term blood sugar control situation needs to be reflected by HbA1C. HbA1C is an excellent indicator for detecting early diabetes. These patients have milder conditions. The originally slightly higher blood glucose often falls back to the normal range after starvation for a period of time. Therefore, when measuring blood glucose on a fasting basis, such patients are often missed, but HbA1C does not. This shortcoming in 2009, the American Diabetes Association proposed "glycated hemoglobin" >= 6.5% as the diagnostic criteria for diabetes. Therefore, "glycated hemoglobin" is a new diagnostic tool in addition to being used as a blood glucose tracking indicator for diabetes. HbA1C (glycated hemoglobin) has been widely used in diabetes patients who need to monitor blood glucose levels in recent years. It can reflect the blood sugar control status about one month before blood collection, and can be used to supervise the blood sugar control situation. The basis of the dose.
於是，本實驗針對糖尿病小鼠在未接受及接受不同劑量APi投藥下，檢測其血液中糖化血色素(HbA1c)含量。圖5之結果顯示，STZ明顯升高HbA1c，與Sham比較時，有顯著的差異。投藥APai (E10, E20, E40, E80 mg/kg)可降低菸鹼醯胺-鏈佐黴素所誘導第II型糖尿病小鼠血液中HbA1c升高現象，其中以E40 mg/kg連續投藥28天的效果最佳。Therefore, in this experiment, the diabetic mice were tested for their glycated hemoglobin (HbA1c) content in the blood without receiving and receiving different doses of APi. The results in Figure 5 show that STZ significantly increased HbA1c, which was significantly different when compared to Sham. APai (E10, E20, E40, E80 mg/kg) can reduce the increase of HbA1c in the blood of type II diabetic mice induced by nicotinamide-streptavidin, including 28 days of continuous administration at E40 mg/kg. The best results.
綜合以上之實驗結果，本發明之穿心蓮有機溶劑萃取物活性成分組成物具有減輕由菸鹼醯胺-鏈佐黴素所誘導第II型糖尿病的病癥，且能有效調控糖尿病鼠之血糖，尤其以40 mg/kg之劑量所達到的效果最為顯著。因此，本發明之穿心蓮有機溶劑萃取物活性成分組成物可用於研發製造天然降血糖藥物或保健食品。Based on the above experimental results, the active ingredient composition of the andrographis paniculata organic solvent extract of the present invention has a condition for alleviating type II diabetes induced by nicotinamide-streptinomycin, and can effectively regulate blood sugar of diabetic rats, especially The effect achieved by the 40 mg/kg dose was the most significant. Therefore, the active ingredient composition of the Andrographis paniculata organic solvent extract of the present invention can be used for research and development of a natural hypoglycemic drug or a health food.
無no
圖1為混合標準物溶液於、及下測得之多重層析圖譜，圖中標示穿心蓮內酯（A）、新穿心蓮內酯(NA)及去氧去氫穿心蓮內酯(DDA)之吸收高峰位置。Figure 1 shows the multiple chromatograms of the mixed standard solution at and below. The figure shows the absorption peak of andrographolide (A), neoandrographolide (NA) and deoxyhydroandrographolide (DDA). position.
圖2係顯示各種劑量(E20, E40, E80 mg/kg)之本發明穿心蓮有機溶劑萃取物APai對於菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠的飲水量(A)及飲食量(B)的影響。Figure 2 is a graph showing the amount of water (A) and diet of the penicillin-chainomycin-induced type II diabetic mice in various doses (E20, E40, E80 mg/kg) of the present invention. The impact of quantity (B).
圖3係顯示各種劑量(E20, E40, E80 mg/kg)之本發明穿心蓮有機溶劑萃取物APai對於菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠之口服葡萄糖耐受性試驗的影響。各數值以平均值± SEM表示。## P ＜ 0.01係相較於正常動物組(Sham組)。* P ＜ 0.05, ** P ＜ 0.01, *** P＜ 0.001係相較於STZ誘導處理組。Figure 3 is a graph showing the oral glucose tolerance test of the penicillin organic solvent extract APai of the present invention for various doses (E20, E40, E80 mg/kg) for nicotinicinamide-streptomycin-induced type II diabetic mice. influences. Each value is expressed as mean ± SEM. ## P < 0.01 is compared to the normal animal group (Sham group). * P < 0.05, ** P < 0.01, *** P < 0.001 compared to the STZ induction treatment group.
圖4係顯示各種劑量(E20, E40, E80 mg/kg)之本發明穿心蓮有機溶劑萃取物APai對於菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠在28-天重複口服投藥之血糖值的影響。各數值以平均值± SEM表示。## P ＜ 0.01,## P ＜ 0.001係相較於正常動物組(Sham組)。* P ＜ 0.05, ** P ＜ 0.01, *** P＜ 0.001係相較於STZ誘導處理組。Figure 4 is a diagram showing that various doses (E20, E40, E80 mg/kg) of the pericardium organic solvent extract APai of the present invention are repeated for oral administration in a 28-day period for a nicotine guanamine-streptidomycin-induced type II diabetic mouse. The effect of blood sugar levels. Each value is expressed as mean ± SEM. ## P < 0.01, ## P < 0.001 is compared to the normal animal group (Sham group). * P < 0.05, ** P < 0.01, *** P < 0.001 compared to the STZ induction treatment group.
圖5係顯示各種劑量(E20, E40, E80 mg/kg)之本發明穿心蓮有機溶劑萃取物APai對於菸鹼醯胺-鏈佐黴素誘導第II型糖尿病小鼠在28-天重複口服投藥之HbA1c值的影響。各數值以平均值± SEM表示。## P ＜ 0.01係相較於正常動物組(Sham組)；* P ＜ 0.05, ** P ＜ 0.01係相較於STZ誘導處理組。Figure 5 is a diagram showing that various doses (E20, E40, E80 mg/kg) of the pericardium organic solvent extract APai of the present invention are repeated for oral administration in a 28-day repeated injection of nicotine indoleamine-streptidomycin-induced type II diabetic mice. The effect of the HbA1c value. Each value is expressed as mean ± SEM. ## P < 0.01 is compared with the normal animal group (Sham group); * P < 0.05, ** P < 0.01 compared with the STZ induction treatment group.
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