1353843 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種醫藥组合物，尤指一種適於預防或治 療滕缺血後再灌注病變（目前世界神經醫學中風標準實驗模 5 式）之醫藥組合物。 【先前技術】 腦中風是成年人最常見的腦部疾病，也是造成中老年人 殘廢的主要原因。數十年來腦中風疾病一直在國人主要死亡 10原因中榜上名列前茅’從民國五十二年至民國七十一年，腦 中風一直是十大死亡原因的第一位。根據榮民總醫院的調 查’台灣腦中風盛行率（新舊病人皆算在内）在三十六歲以 上成年人是千分之十六其中一年新增加的腦中風病例約千 分之二。台灣地區居民平均壽命逐漸增加，老年人口也不斷 15增加’腦中風發生率也偏高。 不管腦中風是因為腦血管阻塞或是腦血管破裂出血所 引起’皆會引起局部性或廣泛性的腦缺血’嚴重的會造成腦 細胞死亡’亦即所謂的腦梗塞。目前在診斷腦缺血，甚至腦 梗塞’進步相當快速。利用功能性核磁共振攝影，在腦血管 20阻塞一個小時内即可診斷出來，但卻尚缺乏快速而有效的治 療方法。目前臨床上主要以血液稀釋來加速局部腦循環，改 善部分缺血’但此西方神經醫學臨床藥物療效並不佳。 在傳統中藥中有許多治腦之醫藥組合物，有其臨床效 5 ^53843 用。但這些醫藥組合物很少經動物證實對缺血性腦損傷具保 護作用，本發明即利用國際認同的優良缺血性腦損傷動物模 式筛選出對中風之預防及治療效果最佳之醫藥組合物。 【發明内容】 本發明之主要目的係在提供一種醫藥組合物，俾能對急 性腦缺氧造成之腦組織損傷具保護或治療作用。 本發明之另一目的係在提供一種醫藥組合物，俾能對腦 缺血所造成之腦梗塞體積具有顯著縮小之效果。 10 為達成上述目的’本發明用於預防或治療腦缺血後再灌 注病變（目前世界神經醫學中風標準實驗模式）之醫藥組合 物含有高麗紅參以及天雄。 本發明醫藥組合物中藥材之重量份無限制，較佳為含有 高麗紅參3至5重量份以及天雄2至4重量份。 15 【實施方式】 為能讓貴審查委員能更瞭解本發明之技術内容，特舉 數較佳具體實施例說明如下。 本發明醫藥組合物對腦缺損，腦栓塞之預防與治療效果 20 之實驗過程步驟如下·· (1)實驗動物 採用450公克大老鼠作為實驗動物（Sprague-Dawly rats)。 6 1353843 (2)動脈結紮再灌流局部腦缺血模式（目前世界神經醫學中 風標準實驗模式） 腦栓塞之產生是採用右側中大腦動脈及雙側頸動脈結 紮方式。動物在用水合氣搭（chloral hydrate)(濃度為每公斤 5體重400毫克）腹腔注射麻醉後，即在右側眼眶及外耳道中 間作皮膚切開並扭開顳肌然後把顴弓嘴側部顳骨鱗部打開 一個小洞’在顯微鏡下找出中大腦動脈。在下皮質靜脈的上 方處用10個零之細線結紫中大觸動脈後，即馬上把雙側頸動 脈用非創性血管夾夾閉。測量腦梗塞體積動物組，即於結紮 10 60分鐘後，用顯微刀解開結紮的中大腦動脈之細線，使中大 腦動脈再新灌注血流外，頸動脈之血管夾亦移除，使血液流 通。然後 把頭部及頸部傷口縫合，並使動物恢復清醒。 (3)大腦梗塞體積的測量 動物在動脈結紮後48小時，即再用水合氣醛（chl〇ral 15 hydrate)麻醉，並用每分鐘150毫升的生理食鹽水經由心臟灌 注大膘。動物在斷頭取出大滕後，便置於5它生理食鹽水中， 並切成2mm厚的大腦切片，放置於37它的2%1^(：：液中3〇分 鐘，此時存活組織呈紅色，壞死組織則成白色。這些壞死組 織隨即放置於固；t液中，並拍照存檔，再用影像分㈣統來 20 量取腦梗塞的面積及體積。 (4 )灌食動物 將藥材製備成水溶液後，依動物鱧重比例每天早晚各灌 食動物-次。實驗分二階段，第—階段：於動脈結紮前三天 開始每日早晚各灌食動物一:欠’再進行结紫手術。手術當日 1353843 於血管結紫前及血液再灌流後也各灌食一次。第二階段：结 紮當日血液再灌流後，動物甦醒後，灌食動物一次。第二天 早晚各灌食一次，第三天早上再灌食一次，晚上進行斷頭取 出大腦》所有實驗用藥材分十組，製備詳述如下： 5 實施例一 取藥材丹參(3g)、蒼朮（3g)、茯苓(3g)、生草（3g)、當歸 (3g)、川芎（3g)、赤芍（3g)、地黃（3g)、黃耆（l〇g)、肉桂子（5g)、 乾薑（3g)、天雄（3g)、以及黃芩（2g)，將上述藥材分別進行切 片處理後，與水1800毫升，一起以加熱萃取方式進行藥液之 10 製備’直至藥液濃縮至約為原體積之30%量後，每曰分三 次，每次2毫升，提供實驗鼠灌服。 實施例二 取藥材黃耆（20g)、當歸（4g)、川芎（4g)、赤芍（4g)、丹參 (4g)、以及銀杏葉（4g)，將上述藥材進行切片處理後，加水 15 1800毫升，以加熱萃取方式進行藥液之製備，直至藥液濃縮 至約為原體精之30%量後，每日分三次，每次2毫升，提供 實驗鼠灌服》 實施例三 取藥材豬苓(5g)、茯苓（5g)、蒼朮（5g)、澤瀉（5g)、肉桂 20子（5g)、乾簦（3g)、天雄（3g)、黃柏（3g)、當歸（2g)、以及黃 耆（10g)’進行切片處理後，加水1800毫升，一起進行加熱 萃取，直至藥液濃缩至約為原體積之30°/。量後’每曰分三 次，每次2毫升，提供實驗鼠灌服。。 實施例四 8 1353843 取藥材甘草（3g)、乾薑（2g)以及天雄（lg)，與水675毫升， 一起進行加熱萃取製備成藥液，直至藥液濃縮至約為原體積 之30%量後，每日分三次，每次2毫升，提供實驗鼠灌服。 實施例五 5 取藥材當歸（3g)、地黃（3g)、桃仁（4g)、紅花（3g)、积殼 (2g)、赤芍（2g)、柴胡（ig)、甘草（ig)、桔梗（1.5g)、川芎（lg) 以及牛膝（3g)’將上述藥材切片後，與水1800毫升，一起進 行加熱萃取製備成藥液，直至藥液濃縮至原艘積之量 後’每曰分三次，每次2毫升’提供實驗鼠灌服》 10 實施例六 取藥材高麗紅參（4g)以及天雄（3g)，打捶成細碎塊後， 以水1000毫升，20%乙醇600毫升，一起浸泡2小時後，進行 加熱萃取使濃缩成原體積之20°/。-30%量，分三次提供實驗者 服用。 15 ( 5 )動物分組 於第一階段中使用動物11組，每組6隻，其中一組為控 制組’灌食食鹽水；另外10組為實驗組，分別灌食上述十種 醫藥組合物。 於第二階段中使用動物6組，每組6隻，其中一組為控制 20 組組’於血管結紮後灌食食鹽水；另外5組為實驗組，分別 於血管結紮後灌食醫藥組合物。 以上實施例在第一階段實驗一對大腦梗塞預防之效 果—如下表所示。 9 1353843 醫藥组合物 平均體積（mm3) 標準誤差值 控制組 203 9.03 實施例一 177 40.2 ' 實施例二 201 34.4 實施例三 190 卜 46.0 - 實施例四 247 523~~~~~ 實施例五 178 36J 實施例六 84.9 6〇 — 在第一階段實驗中，以六種醫藥組合物灌食大白鼠，三 天後再實行右側t大動脈及兩側頸動脈結紮，產生腦梗塞。 實驗結果發現實施例六之醫藥組合物對於所測試之急性腦 5缺血之腦組織損傷有保護作用（即相對於控制組，上述五組 醫藥組合物數值小於控制組，表示腦梗塞範圍有縮小），亦 即對於急性腦梗塞有預防或治療效果。 將上述預防或治療腦梗塞有效的醫藥組合物用以進行 第二階段實驗。在大白鼠右側中大腦動脈以及二側頸動脈結 10紮後餵食，二天後犧牲，取腦切片發現急性腦缺血的腦梗塞 範圍，在實施例六這醫藥組成物之數值，相較於控制組則有 顯著下降的結果’如下表，亦即表示這組醫藥組成物對於急 性腦梗塞有最佳治療效果。 醫藥組合物 平均值 標準誤差值 控制組 206 12.6 實施例六 134 12.5 1353843 上述六種醫藥組合物，實施例六中包含高麗紅參及天 :，其他醫藥組合物皆含有三種以上的生藥成分。本發明對 療、預防腦梗塞都有最佳效果的醫藥組合物，恰為生藥組 5 ，成分最簡單的實施例六，其他多種醫藥組合物中亦個別有 间麗紅參或天雄的成分，如實施例一、實施例四含天雄，但 卻與實施例六之效果不同。 上述實施例僅係為了方便說明而舉例而已，本發明所主 張之權利範圍自應以申請專利範圍所述為準，而非僅限於上 10 述實施例。 【圖式簡單說明】 無 15 【主要元件符號說明】1353843 IX. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition, and more particularly to a method for preventing or treating a reperfusion injury after ischemia (currently the world standard for neuromedical stroke) Pharmaceutical composition. [Prior Art] Stroke is the most common brain disease in adults and is the main cause of disability in middle-aged and elderly people. For a few decades, stroke has been among the top 10 reasons for the death of the country. From the 52nd year of the Republic of China to the 71st year of the Republic of China, stroke has been the number one cause of death. According to the survey of the Veterans General Hospital, the prevalence of stroke in Taiwan (both old and new patients) is 16 per 1,000 adults, and about one in two thousand new cases of stroke. . The average life expectancy of residents in Taiwan has gradually increased, and the elderly population has continued to increase. The incidence of stroke has also been high. Regardless of whether the stroke is caused by cerebral vascular occlusion or cerebral vascular rupture, it can cause local or extensive cerebral ischemia, which can cause brain cell death, which is called cerebral infarction. At present, the diagnosis of cerebral ischemia and even cerebral infarction has progressed quite rapidly. Functional magnetic resonance imaging can be diagnosed within one hour of cerebrovascular occlusion, but there is still a lack of rapid and effective treatment. At present, clinically, blood dilution is used to accelerate local cerebral circulation and improve partial ischemia. However, this western neuromedicine clinical drug is not effective. There are many medical compositions for treating brain in traditional Chinese medicine, which have clinical efficacy 5 ^ 53843. However, these pharmaceutical compositions are rarely confirmed by animals to protect against ischemic brain damage. The present invention utilizes an internationally recognized animal model of ischemic brain injury to screen for a pharmaceutical composition having the best prevention and treatment effect on stroke. . SUMMARY OF THE INVENTION The main object of the present invention is to provide a pharmaceutical composition which has a protective or therapeutic effect on brain tissue damage caused by acute cerebral hypoxia. Another object of the present invention is to provide a pharmaceutical composition which has a significant effect on the volume of cerebral infarction caused by cerebral ischemia. 10 In order to achieve the above object, the pharmaceutical composition for preventing or treating cerebral ischemia and reperfusion lesions (currently the standard model of neuromedical stroke in the world) contains Korean red ginseng and Tianxiong. The weight of the medicinal material in the pharmaceutical composition of the present invention is not limited, and is preferably 3 to 5 parts by weight of Korean red ginseng and 2 to 4 parts by weight of Tianxiong. [Embodiment] In order to enable the reviewing committee to better understand the technical contents of the present invention, a preferred embodiment will be described below. The experimental procedure of the pharmaceutical composition of the present invention for the prevention and treatment of brain defects and cerebral embolism 20 is as follows: (1) Experimental animals 450 g of large mice were used as experimental animals (Sprague-Dawly rats). 6 1353843 (2) Arterial ligation and reperfusion local cerebral ischemia mode (currently the world's neuromedicine stroke standard experimental mode) Cerebral embolism is generated by the right middle cerebral artery and bilateral carotid artery ligation. Animals were anesthetized by intraperitoneal injection of chloral hydrate (concentration: 400 mg/kg body weight). The skin was cut open between the right eyelid and the external auditory canal and the diaphragm was twisted and the sacral scaly was placed on the side of the sacral arch. Open a small hole 'to find the middle cerebral artery under the microscope. Immediately after the upper part of the inferior cortical vein, 10 small thin lines were used to connect the large aorta in the purple, the bilateral cervical artery was clamped with a non-invasive blood vessel clip. The animal group with cerebral infarction volume was measured, that is, after ligation for 10 60 minutes, the thin line of the ligated middle cerebral artery was dissected with a microsurgical knife, and the middle cerebral artery was re-infused with blood flow, and the blood vessel clip of the carotid artery was also removed. Blood circulation. The head and neck wounds are then sutured and the animal is awake. (3) Measurement of cerebral infarct volume Animals were anesthetized with hydrated aldehyde (chl〇ral 15 hydrate) 48 hours after arterial ligation, and sputum was injected through the heart with 150 ml of physiological saline per minute. After the animal was decapitated, it was placed in 5 physiological saline and cut into 2 mm thick brain slices and placed in 37% of its 2% 1^(:: solution for 3 minutes, at which time the viable tissue was present. Red, necrotic tissue is white. These necrotic tissues are placed in the solid; t liquid, and photographed and archived, and then the image is divided into four parts to measure the area and volume of the cerebral infarction. (4) Preparation of the medicinal materials After the aqueous solution is formed, the animals are fed each morning and evening according to the weight ratio of the animals. The experiment is divided into two stages, the first stage: three days before the arterial ligation, the animals are fed one morning and one night: one is owed and then the purple surgery is performed. On the day of surgery, 1353843, each patient was also fed once before the blood vessels were purple and after reperfusion. The second stage: after the blood was reperfused on the day of ligature, the animals were awake and the animals were fed once. The next morning, the animals were fed once a day. Three days in the morning, the rats were fed again, and the brain was decapitated at night. All the experimental herbs were divided into ten groups. The preparation was as follows: 5 Example 1 Take the medicine Danshen (3g), Atractylodes (3g), 茯苓 (3g), raw Grass (3g), Angelica (3g), Chuanxiong 3g), red peony (3g), rehmannia (3g), astragalus (l〇g), cinnamon (5g), dried ginger (3g), Tianxiong (3g), and astragalus (2g), the above herbs After slicing separately, with 1800 ml of water, the preparation of the liquid medicine is carried out by heating extraction method until the liquid is concentrated to about 30% of the original volume, and then each is divided into three times, 2 ml each time, and an experiment is provided. Rats were given the medicinal materials of Astragalus membranaceus (20g), Angelica (4g), Chuanxiong (4g), Radix Paeoniae Alba (4g), Salvia miltiorrhiza (4g), and Ginkgo biloba (4g). Adding water to 15 1800 ml, the preparation of the liquid is carried out by heating extraction until the liquid is concentrated to about 30% of the original essence, and then divided into three times a day, 2 ml each time, to provide experimental rats. Three medicinal herbs, porcine (5g), medlar (5g), atractylodes (5g), Alisma (5g), cinnamon 20 (5g), cognac (3g), Tianxiong (3g), cork (3g), angelica (2g), and astragalus (10g)' After slicing, add 1800 ml of water and heat-extract them together until the liquid is concentrated to about 30 °/ of the original volume. After the 'every three times, each time 2 ml, provide experimental rats to fill.. Example 4 8 1353843 Take the medicinal materials licorice (3g), dried ginger (2g) and Tianxiong (lg), together with water 675ml, The liquid is prepared by heating and extraction until the liquid is concentrated to about 30% of the original volume, and then divided into three times a day, 2 ml each time, to provide the experimental rats for administration. Example 5 5 Take the medicine Angelica (3g), ground Yellow (3g), peach kernel (4g), safflower (3g), pouch (2g), red peony (2g), Bupleurum (ig), licorice (ig), platycodon (1.5g), Chuanxiong (lg) and cattle Knee (3g)' After slicing the above-mentioned medicinal materials, and 1800 ml of water, heat-extracted together to prepare a liquid medicine, until the liquid is concentrated to the original amount of the product, 'each time is divided into three times, each time 2 ml' to provide experimental rats灌服》 10 Example 6 Take the medicinal materials Korean red ginseng (4g) and Tianxiong (3g), smash into fine pieces, then soak with water 1000ml, 20% ethanol 600ml, and soak for 2 hours, then heat extraction Concentrate to 20 ° / original volume. -30% amount, given to the experimenter in three times. 15 (5) Grouping of animals In the first stage, 11 groups of animals were used, 6 in each group, one of which was the control group's feeding of saline; the other 10 groups were experimental groups, and the above ten pharmaceutical compositions were respectively administered. In the second stage, 6 groups of animals were used, 6 in each group, one of which was to control 20 groups' to administer saline after vascular ligation; the other 5 groups were experimental groups, and the medicinal composition was administered after vascular ligation. . The above example demonstrates the effect of a pair of cerebral infarction preventions in the first phase - as shown in the table below. 9 1353843 Pharmaceutical composition average volume (mm3) Standard error value control group 203 9.03 Example 1 177 40.2 'Example 2 201 34.4 Example 3 190 Bu 46.0 - Example 4 247 523~~~~~ Example 5 178 36J Example 6 84.9 6〇—In the first stage experiment, rats were fed with six pharmaceutical compositions, and three days later, the right t-aorta and bilateral carotid arteries were ligated to produce cerebral infarction. The experimental results show that the pharmaceutical composition of the sixth embodiment has a protective effect on the brain tissue damage of the acute brain 5 ischemia test (that is, the value of the above five groups of pharmaceutical compositions is smaller than the control group relative to the control group, indicating that the scope of the cerebral infarction is reduced. ), that is, for the prevention or treatment of acute cerebral infarction. The above-mentioned pharmaceutical composition for preventing or treating cerebral infarction is used for the second-stage experiment. In the right side of the rat, the cerebral artery and the bilateral carotid artery node were fed 10 times, sacrificed two days later, and brain sections were taken to find the range of cerebral infarction of acute cerebral ischemia. The value of the pharmaceutical composition in Example 6 was compared with the control. The group had a significant decrease in the results of the following table, which means that this group of pharmaceutical compositions have the best therapeutic effect on acute cerebral infarction. Pharmaceutical composition Average Standard error value Control group 206 12.6 Example 6 134 12.5 1353843 The above six pharmaceutical compositions, the sixth embodiment contains Korean red ginseng and the day: other pharmaceutical compositions contain more than three kinds of crude drug ingredients. The pharmaceutical composition for treating and preventing cerebral infarction has the best effect, and is just the raw medicine group 5, the simplest embodiment of the sixth embodiment, and the other various pharmaceutical compositions are also individually composed of red ginseng or tianxiong. As in the first embodiment and the fourth embodiment, the effect is different from that of the sixth embodiment. The above-described embodiments are merely examples for convenience of description, and the scope of the claims of the present invention is determined by the scope of the claims, and is not limited to the above embodiments. [Simple description of the diagram] None 15 [Description of main component symbols]