TW202000211A

TW202000211A - Use of composition of Neoandrographolide for improving renal function

Info

Publication number: TW202000211A
Application number: TW107121759A
Authority: TW
Inventors: 林郁進; 張靜雯
Original assignee: 馬來西亞商科鼎國際有限公司
Priority date: 2018-06-25
Filing date: 2018-06-25
Publication date: 2020-01-01
Also published as: TWI721282B

Abstract

The present invention provides the use of Neoandrographolide in preparing a composition for improving renal function. Neoandrographolide is the active component in the composition.

Description

新穿心蓮內酯之組成物用於改善腎功能之應用Application of new andrographolide composition for improving renal function

本發明是有關於新穿心蓮內酯的用途，且特別是有關於新穿心蓮內酯用於製備改善腎功能之組成物的用途。The present invention relates to the use of neo-andrographolide, and particularly to the use of neo-andrographolide for preparing a composition for improving renal function.

糖尿病（Diabetes mellitus）是一種日益嚴重的問題，在發達的國家以及發展中的國家造成許多國民的財務負擔、生活品質下降等問題。糖尿病的特徵是，患者具有高血糖症，且通常伴隨著脂肪及蛋白質的代謝紊亂。一般來說，若不進行治療，糖尿病會引發許多的併發症，例如，心血管疾病、失明、腎功能衰竭和周圍神經損傷等等，嚴重時甚至會造成患者的死亡。就世界衛生組織（World Health Organization；WHO）的統計來說，目前全世界大約有2.5億人患有糖尿病，且到2030年時，患者的數量估計會達到3.6億人。Diabetes (Diabetes mellitus) is an increasingly serious problem that has caused financial problems and a decline in the quality of life of many citizens in developed and developing countries. Diabetes is characterized by patients with hyperglycemia, often accompanied by disorders of fat and protein metabolism. In general, without treatment, diabetes can cause many complications, such as cardiovascular disease, blindness, renal failure and peripheral nerve damage, etc., and even cause death in severe cases. According to the statistics of the World Health Organization (WHO), there are currently about 250 million people worldwide with diabetes, and by 2030, the number of patients is estimated to reach 360 million.

糖尿病可以分為兩種類型，包括第1型糖尿病（胰島素依賴型糖尿病）以及第2型糖尿病（非胰島素依賴型糖尿病）。兩種類型的糖尿病患者的特徵都是其血糖長期高於標準值。糖尿病的病因除了胰島素的分泌不足或甚至不分泌外，胰島素阻抗亦被認為是常見的原因之一。Diabetes can be divided into two types, including type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes). Both types of diabetics are characterized by long-term blood glucose above standard values. In addition to insufficient or no secretion of insulin, insulin resistance is also considered to be one of the common causes of diabetes.

穿心蓮（Andrographis paniculata；AP）是一種具有前景的可用於治療高血糖症的爵床科植物，其在印度、中國大陸、馬來西亞及臺灣等地均有廣泛栽培。穿心蓮的主要藥用部位是乾燥莖與葉子，穿心蓮葉含有多種二萜內酯化合物，包括去氧穿心蓮內酯（Deoxyandrographolide）、穿心蓮內酯（Andrographolide）、新穿心蓮內酯（Neoandrographolide）、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-谷甾醇和磷酸二氫鉀(KH₂ PO₄ )等。另據初步分析，穿心蓮還含有甾醇皂甙、糖類及縮合鞣質等酚類物質。Andrographis paniculata (AP) is a promising genus of plants for the treatment of hyperglycemia, which is widely cultivated in India, China, Malaysia and Taiwan. The main medicinal parts of Andrographis paniculata are dry stems and leaves. Andrographis paniculata leaves contain a variety of diterpene lactone compounds, including Deoxyandrographolide, Andrographolide, Neoandrographolide, and Andrographolide. Ester (Homoandrographolide), Panicolide (Panicolide). It also contains Andrographan, Andrographon, Andrographosterin, β-sitosterol-D-glucoside and so on. In addition to andrographolide, the root also contains 5-hydroxy-7, 8, 2", 3"-tetramethoxyflavonoid (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 potassium dihydrogen phosphate (KH ₂ PO ₄ ), etc. According to preliminary analysis, Andrographis paniculata also contains phenolic substances such as sterol saponins, sugars and condensed tannins.

穿心蓮植物的各種成分，特別是新穿心蓮內酯是否具有特定醫療保健功能是值得再探討及研究的議題。The various components of the Andrographis paniculata plant, especially whether the new andrographolide has specific medical and health care functions, is a topic worthy of further discussion and research.

本發明提供新穿心蓮內酯的新用途，特別是，新穿心蓮內酯在製備可改善腎功能之組成物的用途。經實驗發現，新穿心蓮內酯至少具備可以改善腎功能的能力。此外，新穿心蓮內酯具備同時調降血糖、調降血脂、改善肝功能以及改善腎功能的能力。The present invention provides new uses of new andrographolide, in particular, the use of new andrographolide for preparing a composition which can improve renal function. Experiments have found that neo-andrographolide has at least the ability to improve kidney function. In addition, New Andrographolide has the ability to simultaneously lower blood sugar, lower blood fat, improve liver function and improve kidney function.

本發明揭露新穿心蓮內酯在製備可改善腎功能之組成物的用途，其中所述組成物包括新穿心蓮內酯做為活性成分，所述組成物係用以降低使用者的肌酸酐指數以改善腎臟廓清率。The present invention discloses the use of neo-andrographolide in preparing a composition that can improve renal function, wherein the composition includes neo-andrographolide as an active ingredient, and the composition is used to reduce the user's creatinine index to improve Kidney clearance rate.

本發明另揭露新穿心蓮內酯在製備可改善腎功能之組成物的用途，其中所述組成物包括新穿心蓮內酯做為活性成分，所述組成物係用以降低使用者的尿酸指數。The present invention also discloses the use of neo-andrographolide to prepare a composition that can improve renal function, wherein the composition includes neo-andrographolide as an active ingredient, and the composition is used to reduce the user's uric acid index.

在本發明的一實施例中，所述組成物所包括的新穿心蓮內酯為唯一活性成分。In an embodiment of the invention, the andrographolide included in the composition is the only active ingredient.

在本發明的一實施例中，所述新穿心蓮內酯的最低有效劑量範圍為0.5mg/kg至20mg/kg。In an embodiment of the present invention, the minimum effective dose range of the neo-andrographolide is 0.5 mg/kg to 20 mg/kg.

在本發明的一實施例中，所述新穿心蓮內酯的最低有效劑量範圍為為0.625mg/kg至20mg/kg。In an embodiment of the present invention, the minimum effective dose range of the andrographolide is 0.625 mg/kg to 20 mg/kg.

在本發明的一實施例中，所述使用者為第二型糖尿病病患。In an embodiment of the invention, the user is a type 2 diabetes patient.

在本發明的一實施例中，所述組成物為醫藥組成物。In an embodiment of the invention, the composition is a pharmaceutical composition.

在本發明的一實施例中，所述組成物為一製劑。In an embodiment of the invention, the composition is a preparation.

在本發明的一實施例中，所述製劑為錠劑、片劑、液劑、粉劑、顆粒劑、散劑、丸劑、滴丸劑、膠囊、軟膏、乳膏、乳膠、凝膠、貼片、注射劑、吸入劑、噴劑或是塞劑。In an embodiment of the present invention, the formulation is a tablet, tablet, liquid, powder, granule, powder, pill, drip, capsule, ointment, cream, latex, gel, patch, injection , Inhalation, spray or suppository.

在本發明的一實施例中，所述組成物為一外用製劑。In an embodiment of the invention, the composition is an external preparation.

在本發明的一實施例中，所述外用製劑包括液劑、粉劑、顆粒劑、噴劑、軟膏、乳膏、乳膠、凝膠或是貼片。In an embodiment of the present invention, the external preparation includes liquid, powder, granule, spray, ointment, cream, latex, gel or patch.

在本發明的一實施例中，所述組成物為一口服製劑。In an embodiment of the invention, the composition is an oral preparation.

在本發明的一實施例中，所述口服製劑包括錠劑、片劑、液劑、粉劑、顆粒劑、散劑、丸劑、滴丸劑或是膠囊。In an embodiment of the present invention, the oral preparation includes tablets, tablets, liquids, powders, granules, powders, pills, pills or capsules.

在本發明的一實施例中，所述組成物為一醫藥組成物，且所述組成物更包括醫藥上所使用載劑、稀釋劑或賦形劑做為所述組成物中的非活性成分。In an embodiment of the present invention, the composition is a pharmaceutical composition, and the composition further includes a carrier, diluent or excipient used in medicine as an inactive ingredient in the composition .

在本發明的一實施例中，所述組成物為食品組成物，且所述組成物更包括食品上所使用的增味劑、甜味劑、增稠劑或賦形劑做為所述組成物中的非活性成分。In an embodiment of the present invention, the composition is a food composition, and the composition further includes a flavor enhancer, sweetener, thickener or excipient used in the food as the composition Inactive ingredients.

本發明另提供一種組合物作為改善腎功能的功能性食品的應用，所述組合物包括由新穿心蓮內酯所組成的活性成分；以及食品上所使用的增味劑、甜味劑、增稠劑或賦形劑做為所述組成物中的非活性成分。The present invention also provides the use of a composition as a functional food for improving renal function. The composition includes an active ingredient composed of andrographolide; and a flavor enhancer, sweetener, thickener used in food Agents or excipients are used as inactive ingredients in the composition.

在本發明的一實施例中，所述功能性食品的形式為液體飲料、膠狀品、膠囊、錠劑、片劑或粉末。In an embodiment of the invention, the functional food is in the form of a liquid beverage, a jelly, a capsule, a lozenge, a tablet, or a powder.

基於上述，本發明提供一種新穿心蓮內酯的新用途，其適用於降血糖、降血脂、改善肝功能以及改善腎功能等用途。Based on the above, the present invention provides a new use of new andrographolide, which is suitable for use in lowering blood sugar, lowering blood fat, improving liver function, and improving kidney function.

為讓本發明的上述特徵和優點能更明顯易懂，下文特舉實施例，並配合所附圖式作詳細說明如下。In order to make the above-mentioned features and advantages of the present invention more obvious and understandable, the embodiments are specifically described below in conjunction with the accompanying drawings for detailed description as follows.

本發明實施例中所述的新穿心蓮內酯（Neoandrographolide）可以包括從穿心蓮（Andrographis paniculata）植物中所萃取得到的新穿心蓮內酯或是透過化學合成方式合成的新穿心蓮內酯。新穿心蓮內酯的化學結構式乃是以下列化學式1所示：

化學式1。The neoandrographolide (Neoandrographolide) described in the embodiments of the present invention may include neoandrographolide extracted from the plant of Andrographis paniculata or neo-andrographolide synthesized by chemical synthesis. The chemical structural formula of new andrographolide is shown in the following chemical formula 1:

Chemical formula 1.

本發明實施例中所述的新穿心蓮內酯乃涵括其生理學上之功能衍生物，也就是說本發明實施例中所述的新穿心蓮內酯包含其於醫藥學上可接受之鹽、其於醫藥學上可接受之對映異構體、其於醫藥學上可接受之固態形式（結晶、半結晶或非晶）、其於醫藥學上可接受之多晶型物、其於醫藥學上可接受之溶劑合物或其醫藥學上可接受之代謝物或醫藥學上可接受之前藥。The new andrographolide described in the embodiments of the present invention includes its physiologically functional derivatives, that is to say, the new andrographolide described in the embodiments of the present invention includes its pharmaceutically acceptable salts, Its pharmaceutically acceptable enantiomers, its pharmaceutically acceptable solid form (crystalline, semi-crystalline or amorphous), its pharmaceutically acceptable polymorphs, its pharmacologically acceptable A pharmaceutically acceptable solvate or a pharmaceutically acceptable metabolite or pharmaceutically acceptable prodrug.

本發明一些實施例提供使用新穿心蓮內酯來製備可改善腎功能之組成物的用途，所述組成物包括新穿心蓮內酯做為唯一的藥理活性成分。根據本發明實施例，施用所述組成物可以有效地降低施用者(亦即使用者)的肌酸酐指數以改善腎臟廓清率。根據本發明實施例，施用所述組成物可以有效地降低使用者的尿酸指數。透過上述的各種應用，使用所述組成物更可以有效地對使用者達到改善腎功能的用途。在一些其它實施例中，新穿心蓮內酯是做為組成物中的主要活性成分，但仍可與其它活性成分一起併用來達到改善腎功能的用途。Some embodiments of the present invention provide the use of neo-andrographolide to prepare a composition that can improve renal function, and the composition includes neo-andrographolide as the only pharmacologically active ingredient. According to the embodiment of the present invention, the application of the composition can effectively reduce the creatinine index of the applicator (ie, user) to improve the renal clearance rate. According to the embodiment of the present invention, the application of the composition can effectively reduce the user's uric acid index. Through the above-mentioned various applications, the use of the composition can more effectively achieve the purpose of improving renal function for users. In some other embodiments, neoandrographolide is the main active ingredient in the composition, but it can still be used together with other active ingredients to achieve the purpose of improving renal function.

在一些實施例中，當新穿心蓮內酯是用來降低使用者的肌酸酐指數以改善腎臟廓清率時，其適用劑量為0.5 mg/kg至20mg/kg。也就是說，其最低有效劑量為約0.5mg/kg。在一些實施例中，新穿心蓮內酯適用的有效劑量範圍為0.625mg/kg至20mg/kg。在一些實施例中，新穿心蓮內酯的有效劑量範圍為0.625mg/kg至10 mg/kg。在一些實施例中，新穿心蓮內酯的有效劑量範圍為0.625mg/kg至5 mg/kg。在另一實施例中，當新穿心蓮內酯是用來降低使用者的尿酸指數時，其適用劑量為0.5 mg/kg至20mg/kg。也就是說，其最低有效劑量為約0.5mg/kg。在一些實施例中，新穿心蓮內酯適用的有效劑量範圍為0.625mg/kg至20mg/kg。在一些實施例中，新穿心蓮內酯的有效劑量範圍為0.625mg/kg至10 mg/kg。在一些實施例中，新穿心蓮內酯的有效劑量範圍為0.625mg/kg至5 mg/kg。在本發明一些實施例中，新穿心蓮內酯為所述組成物中的唯一活性成分。換言之，本發明一些實施例中，本案實施例組成物僅使用新穿心蓮內酯作為本案實施例組成物中的藥理活性成分，而穿心蓮萃取物中所包含的其他成分，例如去氧穿心蓮內酯（Deoxyandrographolide）或是穿心蓮內酯（Andrographolide）並不包括在本案實施例組成物中。In some embodiments, when neo-andrographolide is used to reduce the creatinine index of the user to improve the renal clearance rate, the applicable dose is 0.5 mg/kg to 20 mg/kg. In other words, the lowest effective dose is about 0.5 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 20 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 10 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 5 mg/kg. In another embodiment, when neo-andrographolide is used to reduce the uric acid index of the user, the applicable dose is 0.5 mg/kg to 20 mg/kg. In other words, the lowest effective dose is about 0.5 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 20 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 10 mg/kg. In some embodiments, the effective dosage range of neoandrographolide is 0.625 mg/kg to 5 mg/kg. In some embodiments of the present invention, andrographolide is the only active ingredient in the composition. In other words, in some embodiments of the present invention, the composition of the present example only uses new andrographolide as the pharmacologically active ingredient in the composition of the present example, and other ingredients contained in the andrographis paniculata extract, such as deoxyandrographolide ( Deoxyandrographolide) and Andrographolide are not included in the composition of the examples in this case.

在一些實施例中，所述組成物為一醫藥組成物或一製劑。在一些實施例中，所述製劑可以為口服製劑或是外用製劑，但並不以此為限制。在一些實施例中，所述製劑為錠劑、片劑、液劑、粉劑、顆粒劑、散劑、丸劑、滴劑、滴丸劑、膠囊、軟膏、乳膏、乳膠、凝膠、貼片、注射劑、吸入劑、噴劑或是塞劑等等。在一些實施例中，所述口服製劑是指以口服形式施用或可適合於經口投與。出於本發明之目的，口服製劑形式包含膠囊、錠劑、丸劑、顆粒劑、散劑、滴劑及滴丸劑。舉例而言，其製劑可為經包覆或未經包覆、起泡、可溶、口內崩散、腸溶或緩釋錠劑；糖衣錠劑；硬膠囊；軟膠囊；顆粒形式；丸劑；片劑形式調配組成物。較佳地，口服製劑形式為錠劑或膠囊。在一些實施例中，所述外用製劑是液劑、粉劑、顆粒劑、噴劑、軟膏、乳膏、乳膠、凝膠或是貼片。In some embodiments, the composition is a pharmaceutical composition or a preparation. In some embodiments, the preparation may be an oral preparation or an external preparation, but it is not limited thereto. In some embodiments, the formulation is a tablet, tablet, liquid, powder, granule, powder, pill, drop, pill, capsule, ointment, cream, latex, gel, patch, injection , Inhalation, spray or suppository, etc. In some embodiments, the oral formulation refers to oral administration or may be suitable for oral administration. For the purposes of the present invention, oral dosage forms include capsules, lozenges, pills, granules, powders, drops, and pills. For example, the preparation may be coated or uncoated, foamed, soluble, orally disintegrating, enteric-coated or sustained-release tablets; sugar-coated tablets; hard capsules; soft capsules; granular forms; pills; The composition is formulated in the form of tablets. Preferably, the oral preparation is in the form of tablets or capsules. In some embodiments, the external preparation is a liquid, powder, granule, spray, ointment, cream, latex, gel, or patch.

在一些實施例中，所述組成物為健康食品組成物、功能性食品組成物、機能保健食品組成物，甚或是可用於作為預防生理機能改變的食品組成物或搭配改變外表機能的食品組成物等等，但並不以此為限制。在一些實施例中，所述食品組成物更包括添加劑、載劑、稀釋劑或賦形劑做為所述組成物中的其他非活性成分。所述載劑、稀釋劑或賦形劑並無特別限制，且可以配合不同的組合物型態或劑型來進行調整。舉例來說，添加劑和賦形劑包括但不限於防黏劑、防發泡劑、緩衝劑、聚合物、抗氧化劑、防腐劑、螯合劑、黏性調節劑、張力調節劑、調味劑、著色劑、香味劑、遮光劑、懸浮劑、黏合劑、填充劑、塑化劑、潤滑劑及其混合物。在一些實施例中，所述組成物更包括食品上所使用的增味劑、甜味劑、增稠劑或賦形劑做為所述組成物中的非活性成分。In some embodiments, the composition is a health food composition, a functional food composition, a functional health food composition, or even a food composition that can be used as a food composition to prevent physiological function changes or a food composition that changes appearance Wait, but not as a limitation. In some embodiments, the food composition further includes additives, carriers, diluents or excipients as other inactive ingredients in the composition. The carrier, diluent or excipient is not particularly limited, and can be adjusted in accordance with different composition types or dosage forms. For example, additives and excipients include but are not limited to anti-sticking agents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity modifiers, flavoring agents, coloring Agents, fragrances, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants and mixtures thereof. In some embodiments, the composition further includes flavoring agents, sweeteners, thickeners, or excipients used in food as inactive ingredients in the composition.

在一些實施例中，改善腎功能的功能性食品可以使用由新穿心蓮內酯所組成的組合物或包含新穿心蓮內酯的組合物作為主要活性成分。在一些實施例中，所述功能性食品可呈現為液體飲料、膠狀品、膠囊、錠劑、片劑或粉末形式，但並不以此為限制。舉例來說，所述功能性食品可以是任何可藉由口服形式服用或食用的功能性食品。In some embodiments, the functional food for improving renal function may use a composition consisting of neo-andrographolide or a composition containing neo-andrographolide as the main active ingredient. In some embodiments, the functional food may be in the form of a liquid beverage, a jelly, a capsule, a lozenge, a tablet, or a powder, but it is not limited thereto. For example, the functional food may be any functional food that can be taken or consumed by oral administration.

針對本發明實施例中的新穿心蓮內酯的應用與功效，將以下列實施例來做為舉例說明。然而，下列的實施例僅是輔助說明，而並非用以限定本發明。實施例 For the application and efficacy of the new andrographolide in the embodiments of the present invention, the following embodiments will be taken as examples. However, the following examples are only for illustrative purposes, and are not intended to limit the present invention. Examples

在本實施例中，將測試各種劑量之新穿心蓮內酯對於誘導組(誘導所致第2型糖尿病小鼠)的血糖調節能力、生理功能、血液生化物質和一些重要器官組織病理所帶來的影響進行評估。In this example, the effects of various doses of new andrographolide on the blood glucose regulation ability, physiological function, blood biochemical substances and pathology of some important organs and tissues of the induced group (induced type 2 diabetic mice) will be tested. Impact assessment.

雄性ICR小鼠（19-21 g）是購買自台灣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(誘導處理組STZ），是將菸鹼醯胺（Nicotinamide；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。另外，本發明的新穿心蓮內酯（Sigma-Aldrich Chemical Co., Missouri, USA）之投藥量為：NeoL（新穿心蓮內酯低劑量組）: 新穿心蓮內酯2.5mg/kg；NeoM（新穿心蓮內酯中劑量組）：新穿心蓮內酯5.0mg/kg；NeoH（新穿心蓮內酯高劑量組）：新穿心蓮內酯10 mg/kg。上述活性成分是經Tween 20溶解後調整成0.5%甲基纖維素(CMC)溶液。空白組（Sham）則為未經誘導處理的正常小鼠。臨床觀察 Male ICR mice (19-21 g) were purchased from Taiwan BioLASCO Co., Ltd. The mice were fed in the animal center of Universal University of Technology, the temperature was controlled at 22 ± 2°C, the relative humidity was 55 ± 5%, and a 12-hour light/12-hour dark cycle was applied one week before the experiment. For the induction of type II diabetic rats (induction treatment group STZ), nicotine amide (Nicotinamide; Sigma, Saint Louis, MO, USA) saline solution (210 mg/kg bw) was injected intraperitoneally into mice, After 15 minutes, streptozotocin (STZ) (Sigma, 180 mg/kg bw, ip injection) dissolved in citrate buffer (pH 4.5) will be administered to the mice before use. The control group received those two carriers. During the experiment, the food intake and body weight of the experimental animals were recorded once a week. In addition, the dosage of the new andrographolide (Sigma-Aldrich Chemical Co., Missouri, USA) of the present invention is: NeoL (new andrographolide low-dose group): new andrographolide 2.5mg/kg; NeoM (new andrographolide) Medium-dose lactone group): Neo-Andrographolide 5.0mg/kg; NeoH (New andrographolide high-dose group): Neo-Andrographolide 10 mg/kg. The above active ingredient is dissolved in Tween 20 and adjusted to a 0.5% methyl cellulose (CMC) solution. The blank group (Sham) is normal mice without induction treatment. 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。水攝入量檢測 Observe the animal's physical condition at least twice a day, and the interval between each observation is not less than 6 hours to determine the animal's health or death status. Observe the clinical signs of the test animals at least once a day, and record the toxic effects exhibited by the test animals, including the start time and process of such toxic effects. After the test, the surviving mice were sacrificed; afterwards, autopsy was performed and blood samples were taken for serum biochemical analysis. Water intake testing

一般來說，糖尿病患者通常會有「多喝水」的臨床症狀。在本實驗例中，是在40天的期間內分別記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH（10mg/kg）小鼠的水攝入量。實驗結果如圖1所示。Generally speaking, people with diabetes usually have clinical symptoms of "drinking more water". In this experimental example, the blank group Sham, the induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide mid-dose group NeoM (5.0 mg) were recorded in a 40-day period /kg) and the water intake of NeoH (10mg/kg) mice in the high-dose group of andrographolide. The experimental results are shown in Figure 1.

圖1顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的水攝入量檢測結果。如圖1所示，誘導處理組STZ的小鼠的水攝入量在40天的期間內明顯地高於空白組Sham的小鼠。此實驗結果證明經誘導的第2型糖尿病小鼠的水攝入量會比一般正常小鼠來得多。另外，經誘導的第II型糖尿病小鼠在被施用不同劑量的新穿心蓮內酯時，實驗結果發現，不論是在高劑量（10mg/kg）或是低劑量（2.5mg/kg）的情況下，經誘導的第II型糖尿病小鼠的飲水量都會明顯地降低。換言之，新穿心蓮內酯能夠單獨做為活性成分來減輕糖尿病小鼠的臨床病徵。口服葡萄糖耐受性試驗 Fig. 1 shows the results of water intake of various types of andrographolide in the experimental group of the present invention on mice with type 2 diabetes in the induced group. As shown in FIG. 1, the water intake of the STZ mice in the induction treatment group was significantly higher than that of the Sham mice in the blank group during the 40-day period. The results of this experiment prove that the water intake of induced type 2 diabetic mice will be much higher than that of normal mice. In addition, when the induced type 2 diabetic mice were administered different doses of andrographolide, the experimental results found that whether at high dose (10mg/kg) or low dose (2.5mg/kg) , The water consumption of the induced type II diabetic mice will be significantly reduced. In other words, neoandrographolide can be used alone as an active ingredient to alleviate the clinical symptoms of diabetic mice. Oral glucose tolerance test

在本實驗例中，是進行口服葡萄糖耐受性試驗，來評估周邊葡萄糖利用率。在投藥本發明之新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH（10mg/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小時的血糖值。給予葡萄糖(2 g/kg) 30、60、90、120、150、180分鐘後，採集血液樣本測定樣本中的血糖濃度。實驗結果如圖2所示。In this experimental example, an oral glucose tolerance test was conducted to assess peripheral glucose utilization. In the neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/kg) and neo-andrographolide high-dose group NeoH (10 mg/kg) administered for 30 minutes Afterwards, a blood sample is collected before glucose administration to measure the blood glucose concentration in the sample, which is the blood glucose value at 0 hours. After giving glucose (2 g/kg) for 30, 60, 90, 120, 150, and 180 minutes, a blood sample was collected to measure the blood glucose concentration in the sample. The experimental results are shown in Figure 2.

圖2顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的口服葡萄糖耐受性試驗的結果。在圖2中，各數值以平均値±SEM（平均標準誤差）來表示，其中^### P＜0.001是相較於空白組Sham；*P＜0.05，**P＜0.01，***P＜0.001是相較於誘導處理組STZ。如圖2的實驗結果所示，誘導處理組STZ小鼠的血糖値明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠的葡萄糖耐受性較正常小鼠來得差。另外，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）在0至3小時內的血糖値都明顯低於誘導處理組STZ。本發明的新穿心蓮內酯可用以改善經誘導的第2型糖尿病小鼠的低葡萄糖耐受性。換言之，本發明的新穿心蓮內酯可用以提高經誘導的糖尿病小鼠的葡萄糖耐受性。空腹血糖測定 FIG. 2 shows the results of oral glucose tolerance test of various dosages of andrographolide on the type 2 diabetic mice in the induced group of the experimental example of the present invention. In Figure 2, each value is expressed as an average value ± SEM (mean standard error), where ^### P<0.001 is compared to the blank group Sham; *P<0.05, **P<0.01, ***P <0.001 is compared to STZ in the induction treatment group. As shown in the experimental results of FIG. 2, the blood glucose value of STZ mice in the induction treatment group was significantly higher than that of the blank group Sham. The results of this experiment prove that the induced glucose tolerance of type 2 diabetic mice is worse than that of normal mice. In addition, the three-dose group (NeoL, NeoM, NeoH) of the new andrographolide (NeoL, NeoM, NeoH) had significantly lower blood glucose values within 0 to 3 hours than the STZ in the induction treatment group. The new andrographolide of the present invention can be used to improve the low glucose tolerance of induced type 2 diabetic mice. In other words, the new andrographolide of the present invention can be used to improve glucose tolerance in induced diabetic mice. Fasting blood glucose measurement

在本實驗例中，是在42天的期間內分別記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的空腹血糖値。實驗結果如圖3所示。In this experimental example, the blank group Sham, the induction treatment group STZ, the neo-andrographolide low-dose group NeoL (2.5 mg/kg), the neo-andrographolide mid-dose group NeoM (5.0 mg) were recorded during the 42-day period /kg) and the fasting blood glucose values of NeoH mice in the new high-dose andrographolide group. The experimental results are shown in Figure 3.

圖3顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的空腹血糖值測定的結果。在圖3中，各數值以平均値±SEM（平均標準誤差）來表示，其中^### P＜0.001是相較於空白組Sham；*P＜0.05，**P＜0.01，***P＜0.001是相較於誘導處理組STZ。如圖3的實驗結果所示，誘導處理組STZ小鼠的空腹血糖値在0-42天都明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠的葡萄糖耐受性較正常小鼠來得差。另外，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）在投藥第七天以後的空腹血糖值皆明顯低於誘導處理組STZ。換言之，本發明的新穿心蓮內酯可用以降低經誘導的糖尿病小鼠的空腹血糖值。從實驗看來，本發明的新穿心蓮內酯可用以降低空腹血糖值而改善經誘導的第2型糖尿病小鼠的血糖升高問題。而且從目前實驗最低有效劑量範圍為2.5mg/kg至10mg/kg的範圍來看，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）均相當有效。以線性外推法預測其可能可以適用的最低有效劑量可介於0.5 mg/kg至20mg/kg的範圍之間，也可介於0.625 mg/kg至20mg/kg的範圍之間。糖化血色素（ HbA1c ）測定 Fig. 3 shows the results of determination of fasting blood glucose levels of type 2 diabetes mice in the induced group with various doses of andrographolide in the experimental example of the present invention. In Figure 3, each value is expressed as an average value ± SEM (mean standard error), where ^### P<0.001 is compared to the blank group Sham; *P<0.05, **P<0.01, ***P <0.001 is compared to STZ in the induction treatment group. As shown in the experimental results of FIG. 3, the fasting blood glucose values of STZ mice in the induction treatment group were significantly higher than those in the blank group from 0 to 42 days. The results of this experiment prove that the induced glucose tolerance of type 2 diabetic mice is worse than that of normal mice. In addition, the fasting blood glucose values of the three dose groups of neo-Andrographolide (NeoL, NeoM, NeoH) after the seventh day of administration were significantly lower than those of the induction treatment group STZ. In other words, the novel andrographolide of the present invention can be used to reduce the fasting blood glucose value of induced diabetic mice. From the experimental point of view, the novel andrographolide of the present invention can be used to reduce the fasting blood glucose value and improve the problem of induced blood glucose rise in type 2 diabetic mice. And from the current experimental minimum effective dose range of 2.5mg/kg to 10mg/kg, the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) are quite effective. Linear extrapolation predicts that the lowest effective dose that may be applicable may be in the range of 0.5 mg/kg to 20 mg/kg or 0.625 mg/kg to 20 mg/kg. Determination of glycated hemoglobin ( HbA1c )

「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 the red blood cells in the human blood contain hemoglobin. When glucose in the blood enters the red blood cells and combines with heme, glycated hemoglobin is formed. Generally, the average life span of red blood cells is 120 days. Glucose is not easy to fall off when attached to hemoglobin. Therefore, checking the concentration of glycated hemoglobin in the blood can reflect the blood glucose control in the body for the last 2-3 months. The biggest difference between HbA1C and blood glucose is that the blood glucose value only represents the blood glucose state at the time of blood draw, and the blood glucose control situation for a longer period of time must be reflected by HbA1C. HbA1C is an excellent indicator for detecting early diabetes. These patients have a milder condition. The slightly higher blood sugar often returns to the normal range after a period of starvation. Therefore, when measuring blood sugar on an empty stomach, such patients are often missed. However, HbA1C has no This shortcoming In 2009, the American Diabetes Association proposed to use "glycated hemoglobin" >= 6.5% as the diagnostic criteria for diabetes. Therefore, in addition to being used as a blood glucose tracking index for diabetes, "glycated hemoglobin" is also a new diagnostic tool. HbA1C (glycated hemoglobin) has been widely used in diabetic patients who need to monitor blood glucose in recent years. It can reflect the blood glucose control status about one month before blood collection, and can be used to monitor the situation of blood glucose control, and can also be used as an adjustment. The basis of the dose.

在本實驗例中，是在連續投藥42天後記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的糖化血色素（HbA1c）的數值。實驗結果如圖4所示。In this experimental example, the blank group Sham, induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/ kg) and the value of glycated hemoglobin (HbA1c) in NeoH mice in the new high-dose andrographolide group. The experimental results are shown in Figure 4.

圖4顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的糖化血色素（HbA1c）的影響結果。在圖4中，各數值以平均値±SEM（平均標準誤差）來表示，其中^### P＜0.001是相較於空白組Sham； ***P＜0.001是相較於誘導處理組STZ。如圖4的實驗結果所示，誘導處理組STZ小鼠在42天後的HbA1c數值明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠的血糖控制較正常小鼠來得差。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的HbA1c數值皆明顯低於誘導處理組STZ。換言之，本發明的新穿心蓮內酯可用以改善經誘導的第2型糖尿病小鼠的血糖控制不佳的問題。而且從目前實驗最低有效劑量範圍為2.5mg/kg至10mg/kg的範圍來看，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）均相當有效。以線性外推法預測其可能可以適用的最低有效劑量可介於0.5mg/kg至20mg/kg的範圍之間，也可介於0.625 mg/kg至20mg/kg的範圍之間。麩胺酸苯醋酸轉氨基酵素（ Aspartate Aminotransferase ； AST ）測定 Fig. 4 shows the results of the effects of various doses of andrographolide on the glycated hemoglobin (HbA1c) of type 2 diabetic mice in the experimental group of the present invention. In FIG. 4, each value is expressed as an average value ± SEM (mean standard error), where ^### P<0.001 is compared to the blank group Sham; ***P<0.001 is compared to the induction treatment group STZ. As shown in the experimental results of Figure 4, the STZ mice in the induction treatment group had significantly higher HbA1c values after 42 days than the blank group Sham. The results of this experiment prove that the blood glucose control of the induced type 2 diabetic mice is worse than that of normal mice. In addition, after 42 days of continuous administration, the HbA1c values of the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) were significantly lower than those of the induction treatment group STZ. In other words, the novel andrographolide of the present invention can be used to improve the problem of poor blood glucose control in induced type 2 diabetic mice. And from the current experimental minimum effective dose range of 2.5mg/kg to 10mg/kg, the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) are quite effective. Linear extrapolation predicts that the lowest effective dose that may be applicable may be in the range of 0.5 mg/kg to 20 mg/kg or 0.625 mg/kg to 20 mg/kg. Determination of glutamate phenylacetate aminotransferase ( Aspartate Aminotransferase ; AST )

一般來說，第2型糖尿病患者在臨床上常見有非酒精性脂肪肝，進而容易造成肝細胞受損及肝功能的下降。麩胺酸苯醋酸轉氨基酵素（Aspartate Aminotransferase； AST）主要存在於肝臟、心肌，骨骼肌及紅血球中的酵素。當肝臟細胞被破壞或受損時，AST酵素會釋出並進入到血液中。因此，透過血液測試能夠知道肝功能是否有受到影響。In general, non-alcoholic fatty liver is common in patients with type 2 diabetes, which is likely to cause liver cell damage and liver function decline. Aspartate Aminotransferase (AST) is an enzyme mainly found in liver, heart muscle, skeletal muscle and red blood cells. When liver cells are destroyed or damaged, AST enzymes are released and enter the bloodstream. Therefore, blood tests can tell whether liver function is affected.

在本實驗例中，是在連續投藥42天後記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的AST指數。實驗結果如圖5所示。In this experimental example, the blank group Sham, induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/ kg) and the AST index of NeoH mice in the new high-dose andrographolide group. The experimental results are shown in Figure 5.

圖5顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的麩胺酸苯醋酸轉氨基酵素（AST）指數的影響結果。在圖5中，各數值以平均値±SEM（平均標準誤差）來表示，其中^# P＜0.05是相較於空白組Sham；*P＜0.05是相較於誘導處理組STZ。如圖5的實驗結果所示，誘導處理組STZ小鼠在42天後的AST數值明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠的肝功能明顯較正常小鼠來得差。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的AST數值都略低於誘導處理組STZ。其中，新穿心蓮內酯低劑量組NeoL（2.5mg/kg）的AST數值降低的最為明顯。此實驗結果表明了本發明的新穿心蓮內酯具備了改善肝功能的作用，而且最低有效劑量判斷為2.5mg/kg，且以線性外推法預測其可能可以適用的最低有效劑量可介於1.25mg/kg至10mg/kg的範圍之間。三酸甘油酯 （ triglyceride ）及總膽固醇（ cholesterol ）測定 FIG. 5 shows the effect of various doses of andrographolide on the glutamate phenylacetate transaminase (AST) index of type 2 diabetic mice in the experimental group of the present invention. In Figure 5, the average value of each Zhi ± SEM (standard error of the mean) is represented, where ^# P <0.05 compared to the control group is Sham; * P <0.05 was induced by treatment group compared to STZ. As shown in the experimental results of Figure 5, the STZ mice in the induction treatment group had significantly higher AST values after 42 days than the blank group Sham. The results of this experiment prove that the induced liver function of type 2 diabetic mice is significantly worse than that of normal mice. In addition, after 42 days of continuous administration, the AST values of the three dose groups (NeoL, NeoM, NeoH) of neo-andrographolide were slightly lower than those of the induction treatment group STZ. Among them, the AST value of NeoL (2.5 mg/kg) in the low-dose group of andrographolide decreased most significantly. The experimental results show that the new andrographolide of the present invention has the effect of improving liver function, and the lowest effective dose is judged to be 2.5mg/kg, and the lowest effective dose that may be applicable by linear extrapolation is 1.25 Between mg/kg and 10mg/kg. Determination of triglyceride ( triglyceride ) and total cholesterol ( cholesterol )

在臨床上，有高達6至8成比例的糖尿病患會合併出現高血壓與高血脂。糖尿病合併高血脂的機轉較為複雜，最常見的型式包括血中三酸甘油脂上昇，高密度脂蛋白膽固醇(HDL-C)下降與低密度脂蛋白膽固醇(LDL-C)增加。因此，對於糖尿病患者來說，三酸甘油酯及總膽固醇的監控也極為重要。Clinically, as many as 6 to 8 percent of diabetes patients will have hypertension and hyperlipidemia. The mechanism of diabetes combined with hyperlipidemia is more complicated. The most common types include increased blood triglycerides, decreased high-density lipoprotein cholesterol (HDL-C) and increased low-density lipoprotein cholesterol (LDL-C). Therefore, for diabetic patients, the monitoring of triglycerides and total cholesterol is also extremely important.

在本實驗例中，是在連續投藥42天後記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的三酸甘油酯及血中總膽固醇數值。實驗結果如圖6及圖7所示。In this experimental example, the blank group Sham, induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/ kg) and the triglyceride and total cholesterol in NeoH mice of the new andrographolide high-dose group. The experimental results are shown in Figure 6 and Figure 7.

圖6顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的三酸甘油酯（triglyceride）數值的影響結果。在圖6中，各數值以平均値±SEM（平均標準誤差）來表示，其中^## P＜0.01是相較於空白組Sham；**P＜0.01，***P＜0.001是相較於誘導處理組STZ。如圖6的實驗結果所示，誘導處理組STZ小鼠在42天後的血中三酸甘油酯數值明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠具有高血脂、高膽固醇的現象。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的三酸甘油酯（triglyceride）數值皆低於誘導處理組STZ。其中，新穿心蓮內酯中劑量組NeoM（5.0mg/kg）及新穿心蓮內酯高劑量組NeoH（10mg/kg）的三酸甘油酯（triglyceride）的數值最低。此實驗結果表明了本發明的新穿心蓮內酯具有降低三酸甘油酯的作用，且具有劑量依存性（Dose-dependent Effect），而其最低有效劑量為2.5mg/kg。FIG. 6 shows the effect of various doses of andrographolide on the triglyceride value of type 2 diabetic mice in the experimental group of the present invention. In Figure 6, each value is expressed as an average value ± SEM (mean standard error), where ^## P<0.01 is compared to the blank group Sham; **P<0.01, ***P<0.001 is compared to Induction treatment group STZ. As shown in the experimental results of FIG. 6, the STZ mice in the induction treatment group had significantly higher blood triglyceride values after 42 days than the blank group Sham. The results of this experiment prove that the induced type 2 diabetic mice have high blood lipids and high cholesterol. In addition, after 42 days of continuous administration, the triglyceride values of the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) were lower than those of the induction treatment group STZ. Among them, the neo-andrographolide medium-dose group NeoM (5.0 mg/kg) and the neo-andrographolide high-dose group NeoH (10 mg/kg) had the lowest triglyceride values. The experimental results show that the new andrographolide of the present invention has a triglyceride-reducing effect and has a dose-dependent effect, and its minimum effective dose is 2.5 mg/kg.

圖7顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血中總膽固醇（cholesterol）的影響結果。在圖7中，各數值以平均値±SEM（平均標準誤差）來表示，其中^### P＜0.001是相較於空白組Sham；*P＜0.05是相較於誘導處理組STZ。如圖7的實驗結果所示，誘導處理組STZ小鼠在42天後的血中總膽固醇數值明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠具有高血脂、高膽固醇的現象。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的總膽固醇數值都略低於誘導處理組STZ，顯示新穿心蓮內酯具有改善血中總膽固醇的作用，且其最低有效劑量為2.5mg/kg。血清尿酸（ Uric Acid ）測定 FIG. 7 shows the results of the effects of various doses of new andrographolide on the total cholesterol in the blood of the induced type 2 diabetic mice in the experimental example of the present invention. In FIG. 7, each value is expressed as an average value ± SEM (mean standard error), where ^### P<0.001 is compared to the blank group Sham; *P<0.05 is compared to the induction treatment group STZ. As shown in the experimental results of FIG. 7, the total cholesterol in the blood of STZ mice in the induction treatment group after 42 days was significantly higher than that in the blank group Sham. The results of this experiment prove that the induced type 2 diabetic mice have high blood lipids and high cholesterol. In addition, after 42 days of continuous administration, the total cholesterol values of the three dose groups of Neo-Andrographolide (NeoL, NeoM, NeoH) were slightly lower than that of the induction treatment group STZ, showing that Neo-Andrographolide improved the total cholesterol in the blood. Effect, and its lowest effective dose is 2.5mg/kg. Serum uric acid (Uric Acid) assay

許多研究發現，第二型糖尿病和尿酸過高的高危險因素是相同的，其中，最明顯的是超重及肥胖。第二型糖尿病和尿酸過高不單擁有相同的致病病因，尿酸過多更能增加患上二型糖尿病的風險，因此，降低血液內尿酸的水平能預防第二型糖尿病的發病率。引起人體中尿酸過高的原因有很多，舉凡飲食內容、體重、運動、服用藥物、遺傳等因素都可能造成高尿酸血症。血中尿酸大部分是由腎臟排出，一旦尿酸值升高，在腎臟的濃度也會升高，就容易產生尿酸結晶而沉澱在腎臟，造成腎臟的傷害。因此，高尿酸血症容易造成腎功能的下降。Many studies have found that the high risk factors for type 2 diabetes and high uric acid are the same. Among them, the most obvious are overweight and obesity. Type 2 diabetes and high uric acid not only have the same etiology, too much uric acid can increase the risk of type 2 diabetes, so reducing the level of uric acid in the blood can prevent the incidence of type 2 diabetes. There are many causes of excessive uric acid in the human body. For example, dietary content, weight, exercise, taking drugs, genetics and other factors may cause hyperuricemia. Most of the uric acid in the blood is excreted by the kidneys. Once the uric acid value increases, the concentration in the kidneys will also increase, it is easy to produce uric acid crystals and precipitate in the kidneys, causing kidney damage. Therefore, hyperuricemia is likely to cause a decline in renal function.

在本實驗例中，是在連續投藥42天後記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的血清尿酸（serum uric acid）指數。實驗結果如圖8所示。In this experimental example, the blank group Sham, induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/ kg) and the serum uric acid index of NeoH mice in the high-dose group of neo-andrographolide. The experimental results are shown in Figure 8.

圖8顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血清尿酸（serum uric acid）指數的影響結果。在圖8中，各數值以平均値±SEM（平均標準誤差）來表示，其中^### P＜0.001是相較於空白組Sham；**P ＜0.01，***P＜0.001是相較於誘導處理組STZ。如圖8的實驗結果所示，誘導處理組STZ小鼠在42天後的血清尿酸指數明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠具有高尿酸血症的現象。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的血清尿酸指數皆明顯低於誘導處理組STZ。此實驗結果表明了本發明的新穿心蓮內酯能夠降低高尿酸血症患者的尿酸指數，達到改善腎功能之效果。此外，從目前實驗最低有效劑量範圍為2.5mg/kg至10mg/kg的範圍來看，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）均相當有效。以線性外推法預測其可能可以適用的最低有效劑量可介於0.5mg/kg至20mg/kg的範圍之間，也可介於0.625 mg/kg至20mg/kg的範圍之間血清肌酸酐（ serum creatinine ）測定 FIG. 8 shows the effect of various doses of andrographolide on the serum serum uric acid index of type 2 diabetic mice in the induced group in the experimental example of the present invention. In Figure 8, each value is expressed as an average value ± SEM (mean standard error), where ^### P<0.001 is compared to the blank group Sham; **P<0.01, ***P<0.001 is compared In the induction treatment group STZ. As shown in the experimental results of FIG. 8, the serum uric acid index of STZ mice in the induction treatment group after 42 days was significantly higher than that of the blank group Sham. The results of this experiment prove that the induced type 2 diabetic mice have hyperuricemia. In addition, after 42 days of continuous administration, the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) had significantly lower serum uric acid indexes than the induction treatment group STZ. The experimental results show that the new andrographolide of the present invention can reduce the uric acid index of patients with hyperuricemia and achieve the effect of improving renal function. In addition, from the current experimental minimum effective dose range of 2.5mg/kg to 10mg/kg, the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) are quite effective. Linear extrapolation predicts that the lowest effective dose that may be applicable may be in the range of 0.5 mg/kg to 20 mg/kg, or between 0.625 mg/kg and 20 mg/kg serum creatinine ( serum creatinine ) determination

糖尿病腎病變是糖尿病的重要併發症之一，也常導致病人的死亡。腎臟病變進行至較後期時，其過濾功能會逐漸損害，導致無法清理如肌酸酐類等有害物質，進而造成肌酸酐的上升，最後導致腎臟功能衰竭。檢測病患的血清肌酸酐的濃度可用來判別其腎功能是否受到影響。Diabetic nephropathy is one of the important complications of diabetes and often leads to the death of patients. When the kidney disease progresses to a later stage, its filtering function will be gradually damaged, resulting in the inability to clean up harmful substances such as creatinine, which in turn causes the rise of creatinine, and finally leads to kidney failure. Detecting the patient's serum creatinine concentration can be used to determine whether the renal function is affected.

在本實驗例中，是在連續投藥42天後記錄空白組Sham、誘導處理組STZ、新穿心蓮內酯低劑量組NeoL（2.5mg/kg）、新穿心蓮內酯中劑量組NeoM（5.0mg/kg）以及新穿心蓮內酯高劑量組NeoH小鼠的血清肌酸酐（serum creatinine）指數。實驗結果如圖9所示。In this experimental example, the blank group Sham, induction treatment group STZ, neo-andrographolide low-dose group NeoL (2.5 mg/kg), neo-andrographolide medium-dose group NeoM (5.0 mg/ kg) and the serum creatinine index of NeoH mice in the new high-dose andrographolide group. The experimental results are shown in Figure 9.

圖9顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血清肌酸酐（serum creatinine）指數的影響結果。在圖9中，各數值以平均値±SEM（平均標準誤差）來表示，其中^# P＜0.05是相較於空白組Sham；***P＜0.001是相較於誘導處理組STZ。如圖9的實驗結果所示，誘導處理組STZ小鼠在42天後的血清肌酸酐指數明顯高於空白組Sham。此實驗結果證明經誘導的第2型糖尿病小鼠的腎臟廓清率受到誘導藥影響而下降。另外，在連續投藥42天後，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）的血清肌酸酐指數皆明顯低於誘導處理組STZ。此實驗結果表明了本發明的新穿心蓮內酯能夠降低病患的血清肌酸酐的升高作用，進而達到保護腎臟的功能。此外，從目前實驗最低有效劑量範圍為2.5mg/kg至10mg/kg的範圍來看，新穿心蓮內酯的三個劑量組（NeoL、NeoM、NeoH）均相當有效。以線性外推法預測其可能可以適用的最低有效劑量可介於0.5mg/kg至20mg/kg的範圍之間，也可介於0.625 mg/kg至20mg/kg的範圍之間。FIG. 9 shows the effect of various doses of andrographolide on the serum creatinine index of type 2 diabetic mice in the experimental group of the present invention. In Figure 9, the numerical average Zhi ± SEM (standard error of the mean) is represented, where ^# P <0.05 compared to the control group is Sham; *** P <0.001 compared to the process of induction is set STZ. As shown in the experimental results of FIG. 9, the serum creatinine index of STZ mice in the induction treatment group after 42 days was significantly higher than that of the blank group Sham. The results of this experiment prove that the renal clearance rate of induced type 2 diabetic mice is reduced by the influence of the inducing drug. In addition, after 42 days of continuous administration, the serum creatinine index of the three dose groups (NeoL, NeoM, NeoH) of neo-andrographolide was significantly lower than that of the induction treatment group STZ. The results of this experiment show that the new andrographolide of the present invention can reduce the elevated effect of serum creatinine in patients, thereby achieving the function of protecting the kidney. In addition, from the current experimental minimum effective dose range of 2.5mg/kg to 10mg/kg, the three dose groups of neo-andrographolide (NeoL, NeoM, NeoH) are quite effective. Linear extrapolation predicts that the lowest effective dose that may be applicable may be in the range of 0.5 mg/kg to 20 mg/kg or 0.625 mg/kg to 20 mg/kg.

綜上所述，本發明的實驗結果發現，新穿心蓮內酯能夠單獨地改善經誘導的第2型糖尿病小鼠的葡萄糖耐受性、降低空腹血糖及糖化血色素HbA1C，顯示其降血糖的用途。新穿心蓮內酯能夠單獨地降低經誘導的第2型糖尿病小鼠的AST數值，顯示其具備改善肝功能之用途。新穿心蓮內酯能夠單獨地改善經誘導的第2型糖尿病小鼠的三酸甘油酯及血中總膽固醇數值，顯示其降血酯的用途。此外，新穿心蓮內酯能夠單獨地改善經誘導的第2型糖尿病小鼠的血清尿酸指數及血清肌酸酐指數，顯示其具備改善腎功能之用途。In summary, the experimental results of the present invention found that neo-andrographolide alone can improve glucose tolerance, reduce fasting blood glucose and glycated hemoglobin HbA1C in induced type 2 diabetic mice, showing its use for lowering blood glucose. Neoandrographolide alone can reduce the AST value of induced type 2 diabetic mice, showing that it has the purpose of improving liver function. Neo-Andrographolide alone can improve the triglycerides and total cholesterol in blood of induced type 2 diabetic mice, showing the use of its hypotensive esters. In addition, andrographolide can independently improve the serum uric acid index and serum creatinine index of induced type 2 diabetic mice, showing that it has the purpose of improving renal function.

雖然本發明已以實施例揭露如上，然其並非用以限定本發明，任何所屬技術領域中具有通常知識者，在不脫離本發明的精神和範圍內，當可作些許的更動與潤飾，故本發明的保護範圍當視後附的申請專利範圍所界定者為準。Although the present invention has been disclosed as above with examples, it is not intended to limit the present invention. Any person with ordinary knowledge in the technical field can make some changes and modifications without departing from the spirit and scope of the present invention. The scope of protection of the present invention shall be subject to the scope defined in the appended patent application.

Sham‧‧‧空白組STZ‧‧‧誘導處理組NeoL‧‧‧新穿心蓮內酯低劑量組NeoM‧‧‧新穿心蓮內酯中劑量組NeoH‧‧‧新穿心蓮內酯高劑量組Sham‧‧‧Blank group STZ‧‧‧Induction treatment group NeoL‧‧‧New andrographolide low-dose group NeoM‧‧‧New andrographolide medium-dose group NeoH‧‧‧New andrographolide high-dose group

圖1顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的水攝入量檢測結果。圖2顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的口服葡萄糖耐受性試驗的結果。圖3顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的空腹血糖測定的結果。圖4顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的糖化血色素（HbA1c）的影響結果。圖5顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的麩胺酸苯醋酸轉氨基酵素（AST）指數的影響結果。圖6顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的三酸甘油酯（triglyceride）數值的影響結果。圖7顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血中總膽固醇（cholesterol）數值的影響結果。圖8顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血清尿酸（serum uric acid）指數的影響結果。圖9顯示的是本發明實驗例各種劑量之新穿心蓮內酯對於誘導組第2型糖尿病小鼠的血清肌酸酐（serum creatinine）指數的影響結果。Fig. 1 shows the results of water intake of various types of andrographolide in the experimental group of the present invention on mice with type 2 diabetes in the induced group. FIG. 2 shows the results of oral glucose tolerance test of various dosages of andrographolide on the type 2 diabetic mice in the induced group of the experimental example of the present invention. Fig. 3 shows the results of fasting blood glucose measurement of various doses of andrographolide in the experimental group of the present invention on the induced type 2 diabetic mice. Fig. 4 shows the results of the effects of various doses of andrographolide on the glycated hemoglobin (HbA1c) of type 2 diabetic mice in the experimental group of the present invention. FIG. 5 shows the effect of various doses of andrographolide on the glutamate phenylacetate transaminase (AST) index of type 2 diabetic mice in the experimental group of the present invention. FIG. 6 shows the effect of various doses of andrographolide on the triglyceride value of type 2 diabetic mice in the experimental group of the present invention. Fig. 7 shows the results of the effects of various doses of new andrographolide on the total cholesterol in the blood of the induced type 2 diabetic mice in the experimental example of the present invention. FIG. 8 shows the effect of various doses of andrographolide on the serum serum uric acid index of type 2 diabetic mice in the induced group in the experimental example of the present invention. FIG. 9 shows the effect of various doses of andrographolide on the serum creatinine index of type 2 diabetic mice in the experimental group of the present invention.

Sham‧‧‧空白組 Sham‧‧‧ Blank

STZ‧‧‧誘導處理組 STZ‧‧‧Induction treatment group

NeoL‧‧‧新穿心蓮內酯低劑量組 NeoL‧‧‧New andrographolide low-dose group

NeoM‧‧‧新穿心蓮內酯中劑量組 NeoM‧‧‧New Andrographolide Medium Dose Group

NeoH‧‧‧新穿心蓮內酯高劑量組 NeoH‧‧‧New andrographolide high-dose group

Claims

新穿心蓮內酯在製備可改善腎功能之組成物的用途，其中所述組成物包括新穿心蓮內酯做為活性成分，所述組成物係用以降低使用者的肌酸酐指數以改善腎臟廓清率。The use of neo-andrographolide in the preparation of a composition that can improve renal function, wherein the composition includes neo-andrographolide as an active ingredient, and the composition is used to reduce the user's creatinine index to improve renal clearance .

新穿心蓮內酯在製備改善腎功能之組成物的用途，其中所述組成物包括新穿心蓮內酯做為活性成分，所述組成物係用以降低使用者的尿酸指數。The use of neo-andrographolide for preparing a composition for improving renal function, wherein the composition includes neo-andrographolide as an active ingredient, and the composition is used to reduce the uric acid index of the user.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物所包括的新穿心蓮內酯為唯一活性成分。The use as described in item 1 or item 2 of the scope of patent application, wherein the andrographolide included in the composition is the only active ingredient.

如申請專利範圍第1項或第2項所述的用途，其中所述新穿心蓮內酯適用的最低有效劑量範圍為0.5mg/kg至20mg/kg。The use as described in item 1 or item 2 of the patent application scope, wherein the minimum effective dosage range applicable to the new andrographolide is 0.5 mg/kg to 20 mg/kg.

如申請專利範圍第1項或第2項所述的用途，其中所述新穿心蓮內酯適用的最低有效劑量範圍為0.625mg/kg至20mg/kg。The use as described in item 1 or item 2 of the patent application scope, wherein the minimum effective dose range applicable to the new andrographolide is 0.625 mg/kg to 20 mg/kg.

如申請專利範圍第1項或第2項所述的用途，其中所述使用者為第二型糖尿病病患。The use as described in item 1 or 2 of the patent application, wherein the user is a type 2 diabetes patient.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物為一醫藥組成物。The use as described in item 1 or item 2 of the patent application scope, wherein the composition is a pharmaceutical composition.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物為一製劑。The use as described in item 1 or item 2 of the patent application scope, wherein the composition is a preparation.

如申請專利範圍第8項所述的用途，其中所述製劑為錠劑、片劑、液劑、粉劑、顆粒劑、散劑、丸劑、滴丸劑、膠囊、軟膏、乳膏、乳膠、凝膠、貼片、注射劑、吸入劑、噴劑或是塞劑。The use as described in item 8 of the patent application range, wherein the formulation is a tablet, tablet, liquid, powder, granule, powder, pill, drip, capsule, ointment, cream, latex, gel, Patch, injection, inhalation, spray or suppository.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物為一外用製劑。The use as described in item 1 or item 2 of the patent application scope, wherein the composition is an external preparation.

如申請專利範圍第10項所述的用途，其中所述外用製劑包括液劑、粉劑、顆粒劑、噴劑、軟膏、乳膏、乳膠、凝膠或是貼片。The use according to item 10 of the patent application scope, wherein the external preparation includes liquid, powder, granule, spray, ointment, cream, latex, gel or patch.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物為一口服製劑。The use as described in item 1 or item 2 of the patent application, wherein the composition is an oral preparation.

如申請專利範圍第12項所述的用途，其中所述口服製劑包括錠劑、片劑、液劑、粉劑、顆粒劑、散劑、丸劑、滴丸劑或是膠囊。The use as described in Item 12 of the patent application range, wherein the oral preparations include tablets, tablets, liquids, powders, granules, powders, pills, drops, or capsules.

如申請專利範圍第3項所述的用途，其中所述組成物為一醫藥組成物，且所述組成物更包括醫藥上所使用載劑、稀釋劑或賦形劑做為所述組成物中的非活性成分。The use as described in Item 3 of the patent application scope, wherein the composition is a pharmaceutical composition, and the composition further includes a carrier, diluent or excipient used in medicine as the composition Of inactive ingredients.

如申請專利範圍第3項所述的用途，其中所述組成物為一製劑。The use as described in item 3 of the patent application scope, wherein the composition is a preparation.

如申請專利範圍第3項所述的用途，其中所述組成物為一外用製劑。The use as described in item 3 of the patent application scope, wherein the composition is an external preparation.

專利範圍第3項所述的用途，其中所述組成物為一口服製劑。The use according to item 3 of the patent scope, wherein the composition is an oral preparation.

如申請專利範圍第1項或第2項所述的用途，其中所述組成物為食品組成物，且所述組成物更包括食品上所使用的增味劑、甜味劑、增稠劑或賦形劑做為所述組成物中的非活性成分。The use as described in item 1 or item 2 of the patent application scope, wherein the composition is a food composition, and the composition further includes flavoring agents, sweeteners, thickeners or The excipient serves as an inactive ingredient in the composition.

一種組合物作為改善腎功能的功能性食品的應用，所述組合物包括由新穿心蓮內酯所組成的活性成分；以及食品上所使用的增味劑、甜味劑、增稠劑或賦形劑做為所述組成物中的非活性成分。Use of a composition as a functional food for improving renal function, the composition comprising an active ingredient composed of neo-andrographolide; and a flavor enhancer, sweetener, thickener or excipient used in food The agent serves as an inactive ingredient in the composition.

如申請專利範圍第19項所述的應用，其中所述功能性食品的形式為液體飲料、膠狀品、膠囊、錠劑、片劑或粉末。The application as described in item 19 of the patent application scope, wherein the functional food is in the form of a liquid beverage, a jelly, a capsule, a lozenge, a tablet, or a powder.