TWI330533B - Composition for angiogenesis inhibition, neoplasm inhibition,or immunostimulation - Google Patents
Composition for angiogenesis inhibition, neoplasm inhibition,or immunostimulation Download PDFInfo
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- TWI330533B TWI330533B TW092113214A TW92113214A TWI330533B TW I330533 B TWI330533 B TW I330533B TW 092113214 A TW092113214 A TW 092113214A TW 92113214 A TW92113214 A TW 92113214A TW I330533 B TWI330533 B TW I330533B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Medicines Containing Plant Substances (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Description
1330533 五、 發明說明(1) 、【發明所屬之技術領域』 物 本發明係關於一種預防或治療血 。更詳言之,係關於—種組人^關疾病用組成 其衍生物、尤其由擔子结猫楚 3有縠胺酸及/或 生物、或由擔子菌= 得穀胺竣…或其ί 疫 有效成分,而使用於阻止血管 /或其衍生物為 等血管相關疾病之預防或治療。 ,腫瘤、或活化免 血 風濕病 機能有 組織或 細胞移 形成血 長期形 成之埸 胚發生 治癒、 態發生 慢性疾 之增加 症性皮 先前技 管相關 ,糖尿 很大關 器官血 動而增 管腔而 成新血 合受限 、胎盤 炎症之 時,擔 病增生 管形成 或轉移 膚疾病 疾病有 病性視 係。灰 管基底 瘦,與 生成新 管並伸 定。亦 形成等 修復過 負組織 毛細血 為病因 、糖尿 、關節 腫瘤之增殖、 網膜症,乾癬 管形成(vascu 膜被蛋白酶分 細胞外間質接 血管脈之現象 長,但過了生 即’血管形成 通常生理條件 程亦發生。如 回復之重要角 管對組織引起 或病態惡化關 病性視網膜症 炎風濕病、變 ;移’炎症,慢性關節 等,與血管形成或免疫 UriZation)為在動物 解、破壞,使血管内皮 合,血管内皮細胞分化 。—般,在幼兒期或生 長期在體内引起血管形 可在黃體形成、排印、 下觀察到’而在損傷之 此,血管形成在健常狀 色,但在糖屎病等多數 嚴重損傷》 聯之疾病,有惡性腫瘤 、友管形成青光眼、炎 形性關節症、粥狀動脈
1330533 五、發明說明(2) 硬化症、心肌梗塞等阻塞性疾病。 例如1惡性腫瘤增殖時,為獲得腫瘤細胞增殖必要之 s養或氧氣’腫瘤細胞本身以促進血管形成因子誘導血管 形成,通過新形成血管獲得養分之腫瘤細胞更再增瘦。腫 瘤知胞轉移至其他内臟或部位時亦誘導血管形成,腫瘤細 胞隨血流移動。又於糖尿病性視網膜症,被糖尿病之黏性 血液阻塞之毛細血管受損害,網膜發生出血或浮腫,其慢 性化引起網膜氧氣或養分不足,在網膜上或神經系乳頭上 形成新生血管,其周圍形成纖維組織。因該纖維組織而網 膜被拉上(網膜剝離)或網膜血管被撕裂引起(玻璃體)出 血’不久導致兩度視力障礙或失明。 如此’血管形成與各種疾病之發病或進展有深切關 係’以此等疾病之治療與預防為目的之血管形成抑制物質 之探索至今己有很多’現在亦精心研究中。具有血管形成 抑制作用之物質或藥劑先前提示有:硫酸化多糖體(如參 照專利文獻1 ) ’妥拉福明(Traf ermi η)、肝素及類固醇(如 參照專利文獻2及3 )’抗壞血酸醚及其相關化合物(如參照 專利文獻4)’干擾素α或干擾素泠(如參照非專利文獻 1 ),。圭衍生物(如參照專利文獻5 ),鯊魚軟骨萃取物(軟骨 素及黏多糖類)(如參照專利文獻6 ),源自鍵球菌細菌之 多糖類(如參照專利文獻7 ),〇 -取代富馬起羅爾 (Fumagillol)衍生物(如參照專利文獻8),及新瓊脂低聚 糖(如參照專利文獻9 )等。 但至今被k不、檢討為表現血官形成阻止作用之物
1330533 五、發明說明(4) : 發現榖胺酸類、最好具有分子中脫水而環化之構造之穀胺 酸類、尤其穀胺酸酐類及焦穀胺酸類顯著對本發明所^望 之效果奏效’乃至完成本發明。亦即’依據本發明,提供 含有以下式(1)表示之穀胺酸針及/或其衍生物,或以 式(2)表示之焦穀胺酸及/或其衍生物為有效成分之血管 相關疾病之預防或治療用組成物,尤其阻止血管形成用、 抑制腔瘤用、或活化免疫用組成物。 【化學式1】
Η 本發明之組成物之有效成分榖胺酸以榖胺酸針較好’ 而縠胺酸酐以旋光異構體L-穀胺酸酐較好。又穀胺酸酐衍 生物以鹽及/或醯胺較好。 又,本發明之組成物之有效成分穀胺酸以焦穀胺酸 (2-略卷炫闕-5-羧酸)較好,而焦穀胺酸以旋光異構體之[ 體或DL體較好,L體更好。又焦穀胺酸衍生物以鹽及/或 醯胺較好。
第9頁 1330533 五、發明說明(5) 胺酸t發二有關Λ穀胺酸肝及/或其衍生物,及焦穀 式Ϊ i 其衍 其形態可採用天然物,其萃取物 或化學合成物,尤其使用护子菌 、 =末、卒取物或精製物者較好。纟此,擔子菌類即所 "月兹類’以使用由香兹(椎茸)、金針兹、玉兹、鮑备兹 (+尊)、巴西磨益、裂蹄木層孔菌、靈芝(赤芝)、=頭 、雲芝m、舞兹(舞茸)、轉球菌、裂糟菌、白 斗、冬蟲夏草等所構成群中選取1種或2種以上較好。 :子菌類萃取物以使用水及/或親水性有機溶劑自 2子窗類萃取者,或水及/或親水性有機溶劑與疏水性 ^機溶劑萃取者較好。在此,親水性有機溶劑以曱1醇、乙 醇、丙鲷、或丙醇較好,疏水性有機溶劑以己烷或氣仿較 好。 、 依本發明提供之組成物’為血管相關疾病之預防或治 療用組成物,尤其抑制血管形成用、抑制腫瘤用、或活化 免疫用組成物’其較佳形態為飲食品或醫藥品。 四、【實施方式】 以下詳述本發明之組成物及其製造方法。
於本發明之組成物含有之較佳必須成分之穀胺酸酐或 其衍生物,其縠胺酸酐如前記化學構造式表示,為榖胺酸 具有分子中脫水而環化之構造。 又於本發明之組成物含有之較佳必須成分之焦縠胺酸 或其衍生物’其焦穀胺酸(2 -略《»答烧洞-5-叛酸)亦為穀胺
第10頁 1330533 五、發明說明(6) 酸具有分子中脫水而環化之構造。 與本發明有關之穀胺酸酐、焦穀胺酸兩者均由化學合 成法、酵素法、或天然物之水解處理或萃取處理可得,無 論以任何方法調製,穀胺酸部分可以旋光異構體之L-榖胺 酸、D-穀胺酸、或DL-穀胺酸為對象,但由本發明之效果 之觀點以L-穀胺酸或DL-穀胺酸較適合,而以L-穀胺酸最 好。 穀胺酸酐衍生物以鹽及/ 或醯胺較好。此鹽可舉例 如鹽酸鹽、硝酸鹽、硫酸鹽、磷酸鹽等,以鹽酸鹽更適 合。 醯胺之種類可舉例如與醋酸、乳酸、丁酸等低級幾 酸,琥珀酸、蘋果酸、富馬酸等有機酸,碳原子數6〜22 之中鏈脂肪酸(己酸、辛酸、壬酸、癸酸、十二烧酸等)戍 向級脂肪酸(十四酸、十六酸(標櫚酸)、十八酸(硬脂 酸)、油酸、十八碳四烯酸、亞油酸、共輛亞油酸、α _亞 麻酸、7 -亞麻酸、二均-7« -亞麻酸、山荼酸、二十碳五 稀酸、二十二碳五烯酸、二十二碳六稀酸等)之醯胺類。 與菸驗酸、葡萄醛酸、水楊酸等之醯胺類亦好。 又’與各種胺基酸’尤其與構成生體蛋白質之中性胺 基酸(丙胺酸、甘胺酸、纈胺酸、亮胺酸 '異亮胺酸、天 門冬醯胺、榖醯胺),酸性胺基酸(天門冬胺酸、穀胺 酸)’驗性胺基酸(精胺酸、賴胺酸),經基胺基酸(絲胺 酸、蘇胺酸)’環化胺基酸(組胺酸、色胺酸、路胺酸、異 丙胺酸、脯胺酸、羥基脯胺酸),含硫胺基酸(半胱胺酸、
1330533 五、發明說明(7) 胱胺駄、蛋胺酸)等之醯胺類亦適合,與上述各種胺基酸 ^組合構成胜肽之醯胺類,與上述各種胺基酸與葡萄糖、 半礼糖等糖類構成之胺基糖之醯胺類亦可為對象。 焦縠胺酸之衍生物以鹽及/或醯胺較好。此鹽可舉 例如鹽酸鹽、硝酸鹽、硫酸鹽、磷酸鹽、鈉鹽、鉀鹽、鈣 鹽、鎂鹽等,其中以鈉鹽、鹽酸鹽更適合。又,本發明之 焦穀胺酸衍生物亦可以龍為對象,最好為表現可溶於水及 /或親水性有機溶劑且不溶於疏水性有機溶劑之性質者, 其樣式可舉例如與甲醇、乙醇、正丙醇、異丙醇、丁醇等 低級一價酵類,與乳酸、蘋果酸、酒石酸、檸檬酸、葡糖 酸等羥基有機酸類,與乙二醇、丙二醇、甘油、丁四醇、 山梨糖醇等多價醇類,及與蔗糖、葡萄糖、半乳糖、麥芽 糖等糖類之各種酯類。 酿胺以與各種胺基酸,尤其與構成生體蛋白質之中性 胺基酸(丙胺酸、甘胺酸、纈胺酸、亮胺酸、異亮胺酸、 天門冬醯胺、榖醯胺)’酸性胺基酸(天門冬胺酸、穀胺 酸),鹼性胺基酸(精胺酸、賴胺酸),羥基胺基酸(絲胺 酸、蘇胺酸),環化胺基酸(組胺酸、色胺酸、酪胺酸、異 丙胺酸、脯胺酸、羥基脯胺酸),含硫胺基酸(半胱胺酸、 胱胺酸、蛋胺酸)等之醯胺類為適合,與上述各種胺基酸 之組合構成胜肽之酿胺類,與上述各種胺基酸與葡萄糖、 半乳糖等糖類構成之胺基糖之醯胺類亦可為對象。 穀胺酸酐之化學合成可依習知方法(如J. Kol Ion it sch & A.Rosegay; Chemistry and Industry,
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五、發明說明(8) No. 7, P. 1 867, 胺酸之三氟化 生沈澱,接之 酐。又以此L-性合成上述各 焦穀胺酸 例為將L-穀胺 程度加熱處理 °C程度則因外 物以此L-焦穀 學性或酵素性 由天然物 酸、蛋白酶水 製之方法。較 為原料,將此 液,再用有機 製物》本發明 製樣式。 1 9 64 )。其一例為添加亞硫醯二氣於含卜穀 錯酸溶液中進行脫水反應後,加二乙趟使產 在冷部下用二乙趟再結晶以調製L-榖胺酸 穀胺酸酐為起始物質依常法以化學性或酵素 種衍生物。 及其衍生物之化學合成可依習知方法,其一 酸與等重量之水在高壓鍋中以約13〇〜15〇。〇 即可得L-焦榖胺酸,又如強熱至約19〇〜2〇〇 消旋作用而可得DL-焦榖胺酸。又上述衍生 胺酸或DL-焦榖胺醆為起始物質依常法以化 合成即可。 調製與本發明有關之穀胺酸酐,可利用鹽 解源自動植物或魚貝类員之蛋白貪,再分級精 適合之方法為用擔子菌類之子實體或菌絲體 乾燥製成粉末’或用萃取溶劑處理成萃取 溶劑、吸附劑等分級、分部處理成高濃度精 利用此為穀胺酸針及/或衍生物之適合調 &由天然物調製焦穀胺酸時亦與榖胺酸酐相同方法而可 能製成高濃度精製物,並利用此為穀胺酸酐及 或衍生 物之適合調製樣式。 / 在此’擔子菌類最好由香菇(椎茸)、金針兹、玉益、 鮑魚兹(平茸)、巴西蘑菇、裂蹄木層孔菌、靈芝(赤芝)、 猴頭兹、雲芝、蘑菇、舞菇(舞茸)、锈球菌、裂權菌、白
1330533 五、發明說明(9) · 木耳、冬蟲夏草等所構成群中選取1種或2種以上。此等祐 類子實體均人工栽培或多量採取而在市面流通,容易取 得’以生鮮、乾燥物、其粉末或萃取物等提供食用。 又如香菇(椎茸)、雲芝、裂褶菌等其萃取物所含多糖 體己利用為醫藥品。於本發明,由所希望效果之觀點,以 巴西蘑菇、裂蹄木層孔菌、靈芝、猴頭菇、冬蟲夏草等所 構成群中選取1種或2種以上較好,而以巴西蘑菇最好。 蘑兹為蘑兹科(伞菌科)、磨益屬(伞菌屬)之益類,如 巴西蘑菇(Agaricus blazei Murill)、二孢蘑菇 (Agaricus bisporus (Lange)Sing)。前者含多糖體(万 -D-葡聚糖)及多糖蛋白複合體,己知有抗腫瘤作用、血糖 減低作用專。裂蹄木層孔菌(PheHinus iinteus(Berk.
Et Curt. ) T eng)屬刺革菌科,其熱水萃取物之多糖體表 現抗腫瘤作用。靈芝(Ganoderma lucidum (Leyss. Ex Fr.) Karst)屬靈芝菌科’又稱萬年菇,己知其類g及多 糖體之抗過敏作用、抗腫瘤作用、血壓安定化作用,及蛋 白多糖之血糖減低作用等。猴頭菇(Hericium erinaceus (Bull.) Pers)屬猴頭菌科,己知其異々_D_葡聚糖之抗腫 瘤作用、活性氧消除作用。 於本發明,上述擔子菌類之子實體可直接以生鮮或以 乾燥物之任一當做原料使用,但由使用上、保存性及萃取 效率等觀點以乾燥物較好。 又菌絲體可以利用由含適當碳素源與氮素源培養基培 養菌種所得生鮮或乾燥菌絲體,但與子實體相同以乾燥&
1330533 五、發明說明(10) _ 較簡便。又於本發明,除當做此種菌 菌絲體時產生之培養液亦可當做原料料外,生產 縮處理後,供下述溶劑分級等之精製處;:養液經適當漢 於本發明,為由上述擔子菌類之 與本發明有關之穀胺酸酐及/…生:體或隹?體製造 /或其衍生物,使用水及/或親水性有機六;^权,酸及 親水性有機溶劑與疏水性有機溶劑進:二’或水及 之萃取物幾無表現本發明所希望之效 禾親水I·生有機溶劑以曱醇、乙醇、正 〈效 兩鋼較好,疏水性有機溶劑則以己仿2丙醇、或 有機溶劑亦可為與水之混合物,親。親水性 之形態亦適合…取本又兩者混合 J致成分時重要者為,使用水及/《親水性成用:成物之 有機溶劑之混合溶劑獲得以水性成分容Λ體 2卒取物’其次以親水性有機溶 糖類、胺基酸等易溶性志八,* ”方降水冷性更尚之 除脂質類等油性成分。刀 以疏水性有機溶劑分級去 混合使用親水性有機溶劑 比例(容量比),以前者/後者有機冷劑時之混合 好、3/1〜1/1最好。偏離 較好、5/1〜1/5更 須虏八$茬&分玄+ 述範圍時可能減低本發明之必 f成勿之卒取效率或不能獲 := 用量為對子實體或菌絲體之參極:=效果卒取浴劑使 (以重量計算)程度。未達3之萃物、卒取物使用3,倍 崚J倍時卒取物之產率低,反之使 第〗5頁 1330533 五、發明說明(11) 用超過20倍之多量亦不能更再提升萃取效率。 .萃取處理時,使擔子菌類之子實體或菌絲體與上述萃 取溶。劑接觸,在常壓或加壓下,較好〗〜3氣壓下,室溫至 lj〇 C左右,適當攪拌或迥流萃取約丨〇分〜約丨〇小時即得 萃取液。該萃取液用減壓乾燥、冷凍乾燥、喷霧乾燥等 理去除溶劑,以調製擔子菌類萃取物。又上述萃取物以 水性有機溶劑及疏水性有機溶劑分級處理,可得更再提言 本發明必須成分之含量之濃縮物,並再以使用矽膠、活 氧化鋁、矽酸鎂、活性碳、纖维素、離子交換樹脂等吸 劑之色層分析分部處理以製造高濃度精製物。 如上述,由化學合成法或擔子菌類萃取法調製之 酸酐及/或其衍生物及焦穀胺酸及/或其衍生物, 此等之萃取液、萃取物、濃縮物、及精製物,彳直接^ 適當載體、賦形劑、添加物等併用而製成本發明之制^ 管形成用組成物。本發明之抑制血管形成用組成物在 反本發明之意圖下可配合併用各種原料或成分,如 $ 許之載體或食用載體而使用於通常之食品或醫藥品之 劑、防濕劑、防腐劑、強化劑、增稠劑 '乳化劑、 = 止劑、甘味料、酸味料、調味料、著色料、香料等 方 又併用具有血管形成抑制作用之習知屌枓幺*双口口 原枓為本發明之較佳 式之—。 又上述本發明之組成:’亦當做抑制腫瘤或 用組成物而發揮機能,且表現顯著效果。亦即本發 二 成物,作用為血管相關疾病之預防或治療組成物,瘦口攝
第16貞 1330533 五、發明說明(12)
取此組成物除表現企管形成抑制作用外,亦表現抗腫瘤作 用即腫瘤之增殖抑制作用及轉移抑制作用,並更表現免疫 增強作用°又’對於慢性關節風濕病、糖尿病性視網膜 症、乾癖等具有效果,對血管形成青光眼、炎症性皮膚病 病、關節炎風濕病、變形性關節症、粥狀動脈硬化症、心 肌梗塞等阻塞性疾病亦有效。因此,此種組成物可當做異 有上述作用之組成物活用,該組成物之具體樣式可舉例如 飲食品、醫藥品、寵物食料、家畜•家禽用飼料等。尤其 以飲食品及醫藥品為適合。 此飲食品之形態,可將前述擔子菌類乾燥粉末、萃取 物或精製物等直接或將含此等之前述阻止血管形成用組成 物添加於液狀、膠狀、粉狀或固體狀食品,如水果飲料、 清涼飲料、茶、湯、果凍、養樂多、布丁、西點總會、調 味撒籾、味。曾 '醬油、調味汁、美奶玆、烤肉醬等之調味 料、麵類、火腿香腸等畜肉魚肉加工食品、果醬、牛奶, 冰漠淋、奶油乳酪等粉狀、固體狀或液狀乳製品、人造奶 油、麵包、蛋糕、小甜餅等之形態。
又依需要可與糊精、乳糖、澱粉或其加工原料、纖維 素粉等賦形劑、維生素、礦物質、動植物魚貝類之油脂、 蛋白質、糖類、色素、香料、其他上述食用添加劑等加工 成散劑、顆粒劑、丸劑、錠劑等,或以明膠等被覆成膠囊 狀,或做成飲料類,當做營養補助食品或健康食品利^。 此時適合併用具有阻止血管形成作用之習知食用原料之银 成物。又本發明之飲食品之形態極多’不受上述所示例之
1330533 五、發明說明(13) ----- 限定,但以上述營養補助食品或健康食品之形態較好。 於本發明,本發明組成物對飲食品之配合量,因該 食品之種類、形態、使用目的、及配合組成物之種類二來 態等而無法統一規範,添加於一般加工食品類時,以榖‘ 酸酐或焦穀胺酸為基準約〇. 〇 1〜5 0重量%,並以〇. i〜 量%較好。偏離此範圍而較少時以經口攝取之本發明之所4 希望效果小,反之過多時因飲食品種類而損害風味,或無 法調製該飲食品。又本發明組成物直接供食用亦無妨·’’、 、▲本發明之醫藥品之形態,對上述組成物依需^添加不 違反本發明意圖之習知賦形劑或添加劑,依常法加工成 劑、膠囊劑、顆粒劑、散劑、注射劑等製劑。將此經口 予、經腸投予、血管投予、或皮下投予,利用於表現抑^ 血管形成、抑制腫瘤、活化免疫作用中至少丨種效果,並 適用於伴隨血管形成、腫瘤增殖及轉移、免疫能力減低等 引起之各種疾病之預防或治療。本發明組成物之配合量’ ,其形態及上述醫藥用製劑之種類、形態、用法、及用量 等而無法統一設定,但以榖胺酸酐或焦穀胺酸為基準約 0 1〜70重量%。經口投予時之攝取量並無特別限定,以穀· 胺酸針或焦縠胺酸為基準,成人(體重5〇Kg)每曰〇〇丨〜又 2〇g、而每日〇. 1〜i〇g更好。偏離此範圍而較少時所希望 效果減小’反之過多亦不能期望更顯著之效果。 【實施例] 實施例1 粗碎巴西磨兹(Agaricus blazei Murill)之乾燥子實
第18頁 1330533 五、發明說明(14) 體,加氣仿/曱醇=1/1混合液加熱至40 °C進行萃取處理 1小時’得氣仿/曱醇=1/1萃取物。加曱醇於該萃取物 調製甲醇可溶部,再加己烷於此曱醇可溶部提取己烷不溶 部(樣品1 )。其次供己烷不溶部於矽膠管柱色層分析 (si lanised Si 1 icagei 60(矽烷化矽膠60) PF 256 :
Merck 7751'伊默克公司製品,提取液水/曱醇= 7/3) ’調製泮滿三酿j(ninhydrin)陽性反應部份(No.5、6 分部)。其次供該分部於HPLC(Shimpak PREP-ODS(M)、管 柱:§ 20 X 2 50mm、ShimadzuC日本島津製作所製品)、RT 6ml/min、水/ 曱醇=5/;!),調製茚滿三酮陽性反應部份 (Rt=6 〜12min)。再供該分部於 HPLC(Shimpak PREP-ODS(M)、管柱:$ 20x 250mm 'Shimadzu(日本島津 製作所製品)、RT 6ml/min、水)’調製茚滿三酮陽性反應 部份(Rt = 8〜22 min)。此茚滿三酮陽性反應分部再以TLc (Silicagel60 PF254 :Merck 7747、伊默克公司製品,水 /甲醇—1/100)精製’確認含有穀胺酸酐(Rf=〇.41)。又 根據質譜分析法及NMR分析結果,此穀胺酸酐為旋光異構 體之L型體。 實施例2 =蹄木層孔菌之菌種在含葡萄糖及竦(pept〇ne)培養 2,, c,養72小時後採取菌絲體。此菌絲體經乾燥及粉 2理成菌絲體粉末’加己院/乙醇/水=2/3/1混合 溫進行萃取處理3小時得萃取物(樣品2)。該萃取 物再Μ乙_分級處理㈣乙料溶部,以烧分級處理該
第19頁 1330533 五、發明說明(15) 乙醇可溶部調製己烷不溶部。其次,與實施例1相同以石夕 膠管柱層析、HPLC、TLC進行示差、精製處理,由質譜分 析及NMR分析結果確認L-穀胺酸酐之存在。 實施例3 依前述文獻說明方法化學合成L-穀胺酸鹽。亦即加三 氟化醋酸75ml及L-穀胺酸〇· 〇8克分子量於四口燒瓶,授掉 溶解°在攪拌卞徐徐滴加亞硫醯二氯〇. 28克分子量,滴加 終了後經30分鐘時緩緩添加二乙醚35ml使產生沈澱物。其 次於5 C保持1小時後加二乙醚1 〇 〇 m 1 ’重複再結晶,調製 成L-縠胺酸酐鹽酸鹽(樣品3)。 實施例4 於貫施例3 ’除原料L -穀胺酸以D L -穀胺酸替代外餘均 相同處理,調製成DL-縠胺酸酐鹽酸鹽(樣品4)。 實施例5 粗碎巴西蘑菇之乾燥子實體並加水’以常法於8〇〜95 °C進行熱水萃取處理’將該萃取液在減壓下乾燥處理調製 巴西蘑菇熱水萃取物’對該萃取物之4〇重量%水溶液加3倍 (重量)乙醇混合後’提取乙醇液層’減壓乾燥調製得乙^ 可溶物(樣品5)。 比較例1 粗碎巴西蘑菇之乾燥子實體並加水,以常法於8〇〜95 °C進行熱水萃取處理’將該萃取液在減壓下乾燥處理調製 得相當於市售品之巴西蘑菇熱水萃取物(比較樣品丨)。 試驗例1
1330533 五、發明說明(16) 與本發明有關之穀胺酸酐、其衍生物、含此等之各種 加工處理物之血管形成抑制作用,依Passaniti等之方法 (Laboratory Invest. ,Vol.67,P.519 〜528,1992),由 MATRIGEL基質(matrix)( —種細胞培養基質、Becton D i k i nson Labware公司製品)所誘導血管形成之程度調查 之0 亦即,5週齡C 5 7 B L / 6雌性小(白)鼠(由日本查利斯利 巴股份有限公司購入)經1週之預備飼養後,選用健全小鼠 (1組5隻),將下示供試物各0.5ml在冷卻下移植上述小鼠 腹部皮下,移植後第6日取出M ATRIGEL基質觀察血管形成 狀態。 又將M A T RIG E L基質冷;東乾燥後測定重量。再者,將取 出之MATRIGEL基質加純水lml後用Polytron均質器磨碎、 2 00 Orpm遠心分離5分鐘後’其上清液以〇. 2 過濾、膜過 濾,用血紅素檢測-和光(曰本和光純藥股份有限公司製 品)測定血紅素量。 •正常組:MATRIGEL基質 •對照組:MATRIGEL基質、肝素(64單位)、酸性纖維芽 細胞增殖因子(以下簡寫為a-FGF)(l ng/ml) •供試物添加組1 : MATRIGEL基質、肝素(64單位)、 a-FGF(l ng/ml)、樣品3 (800 #g/ml) •供試物添加組2 : MATRIGEL基質、肝素(64單位)、 a-FGF(l ng/ml)、樣品3 (400 g/m 1 ) •供試物添加組3 : MATRIGEL基質、肝素(64單位)、
第21頁 1330533 五、發明說明(17) βg/ml) 、肝素(64單位) βg/ml) 、肝素(6 4單位) βg/ml) 、肝素(6 4單位) βg/ml) 、肝素(6 4單位) a-FGF(l ng/ml)、樣品3 (200 •供試物添加組4 :MATRIGEL基質 a-FGF(l ng/ml)、樣品4 (800 •供試物添加組5 :MATRIGEL基質 a-FGF(l ng/ml)、樣品1 (600 •供試物添加組6 :MATRIGEL基質 a-FGF(l ng/ml)、樣品2 (800 •供試物添加組7 : MATRIGEL基質 a-FGF(l ng/mi)、樣品1 + 樣品3 (各2〇〇 vg/ml) •供試物添加組8 : MATRIGEL基質、肝素(64單位)、 a-FGF(l ng/ml)、樣品5 ( 600 yg/ml) •供試物添加組9 : MATRIGEL基質、肝素(64單位)、 a-FGF(l ng/ml)、比較樣品 1 (8〇〇 //g/ml) 試驗結果示如表1及表2。各表中之數值以、平均 值標準誤差表示。由各表得知對照組較正常组顯著促進 血管形成’ MATRIGEL基質重量及血紅素量均增加。相較於 此’於供試物添加組,樣品3 (L_穀胺酸酐鹽酸鹽)以濃度 依賴性抑制MATRIGEL基質重量及血紅素量之增加,確認可 抑制血·管形成’而樣品4(DL_榖胺酸酐鹽酸鹽)雖較樣品3 =,但亦確認相同之抑制血管形成作用。又、樣品丨(蘑菇 ,物精製物)、被品2 (裂蹄木層孔菌萃取物)亦得知具有 抑制血管形成效果。又比較樣品丨(蘑菇熱水萃取物) 之抑制血管形成效果則小。
第22頁 1330533 五、發明說明(18) 【表1】 MATRIGEL matrix 之重量
No 試驗組別 供試物(# g/ml) MATRIGEL matrix 重量img) n=5 1 正常組 77.7+ 10.1 2 對照組 413.3± 42.5 3 供試物添加組1樣品3 (800) 110.9± 11.4 4 供試物添加組2樣品3 (400) 232.2± 52.7 5 供試物添加組3樣品3 (200) 276.6± 27.6 6 7 供試物添加組4樣品4 (800) 237.3± 30.1 8 供試物添加組5樣品1 (600) 105.0± 12.3 9 供試物添加組6樣品2 (800) 149.4± 24.7 供試物添加組7樣品1/樣品3= 10 1/1 (400) 167.3± 33.2 11 供試物添加組8樣品5 (600) 181.1± 20.2 供試物添加組9比較樣品1 (800) 357.6± 36.2 表2 MATRIGEL matrix中之血紅素量
No 試驗組別 供試物(# g/ml) 血紅素量(mg) n=5 1 正常組 4.6土 1.0 2 對照組 30.4± 2.6 3 供試物添加組1樣品3 (800) 3.9± 0.5 - 4 供試物添加組2樣品3 (400) 15.5± 4.6 5 供試物添加組3樣品3 (200) 21.5± 4.0 〇 7 供試物添加組4樣品4 (800) 13.0± 2.9 8 供試物添加組5樣品1 (600) 4.0± 0.8 9 供試物添加組6樣品2 (800) 5.4+ 0.7 10 供試物添加組7樣品1/樣品3=1/1 (400) 9.3+ 2.2 11 供試物添加組8樣品5 (600) 7.6+ 2.4 供試物添加組9比較樣品1 (800) 27.3± 3.7 第23頁 1330533 五、發明說明(19) 試驗例2 與本發明有關之樣品,用以下方法試驗並評估其抑制 腫瘤增殖作用及抑制腫瘤轉移作用。亦即,由日本理化學 研究所受讓之路易士肺癌(以下簡寫為LLC、Lou i s Lung Cancer)細胞懸浮於磷酸•生理食鹽緩衝液(pH7.4)。另一 方面,6週齡C57BL/6J雌性小鼠(由日本克雷亞股份有限公 司購入)經1週之預備飼養後,取健全小鼠(1組7隻)在戊巴 ' 比多納(n e m b u t a 1 )麻醉下進行小切開,對露出之脾臟注入 ' LLC細胞懸浮液(LLC細胞數1. 0 X 1 05)後,立即縫合小切 開。移植LLC細胞1 2小時後,經口投予巴西蘑茹.萃取物(樣 馨 品1)100 mg/kg(體重)或300 mg/kg(體重)、1日1次、連續 20曰。正常組及對照組(LCC帶癌小鼠)則投予蒸餾水以代 替樣品1。於此試驗期間,癌細胞增殖率以每隱2〜3曰測 定癌組織容積量(用長徑X短徑2/2 )計算。在癌細胞移植後 第2 1日將各組小鼠在乙醚麻醉下,由靜脈以加肝素採血, 用血細胞庫爾特計數器(Coulter counter)測定血中之白 血球數、紅血球數、及血紅素量;另外,宰殺採血後之小 -A蜱取癌組織、肝臟、肺、脾臟及胸腺,測定各組織灸 重量,並以立體顯微鏡計异轉移肺組織之癌細胞集群(〇犷 集落、colony)數。 _ 。。LCC細胞移植小鼠之腫瘤組織容積量,癌組織及各臟 ’ 器之重量,白血球數、紅血球數、血紅素量、及肺轉移集 · 群數分別列如表3、表4、表5。又各表中數值以平均值土 標準誤差表不,顯著性測驗以費雪保護最低效數位測驗
1330533 五、發明說明(20) (Fisher’s Protect LSD Test)進行,並以 P<0.05 為差異 顯著。 【表3】 ..LCC細胞移植小鼠之腫瘤容積量(n= 7)_ 離腦 |對照組 —物組1 供試物組2 供試物(mg/Kg) 樣品1(100) 樣品1(300)
362± 33 461± 94 53肚 108 745± 142 872± 173 1505± 362 164+ 30( *) 247土 52( *) 301土 73(*) 323± 101(*) 346± 108(*) 410± 89( *) 290土 40 307± 64 322± 57( *) 49¾ 115 517± 121(*) 608± 133( *) (注)(* ):與對照組比顯著差異(P < 0.05)。 【表4】
LCC細胞移植小鼠之組織重量(n=7) 離删 正常組 對照組 供試物組1 供試物組2 供試物(mg/Kg) 樣品1(100) 樣品1(300) 起始體重(g) 17.9± 0.30 18.2± 0.21 18.0± 0.23 17.肚 0.25 最終體重(g) 21.0± 0.41 19.9± 0.54 20.3± 0.72 20.0± 0.24 腫瘤重量(mg) — 1872± 604 531± 267* 460± 115* 脾臟(g) 0.07± 0.01* 0.71± 0.03 0.35± 0.02* 0.22± 0.02* 肝臟(g) 1.18± 0.05 1.28± 0.04 1.22± 0.03 1.24± 0.06 肺(mg) 152.8± 4.51 166.8± 9.20 165.0± 6.76 155.0± 5.14 胸腺(mg) 47.0± 5.3 41.6± 10.3 45.2± 4.2 50.5± 3.0 (注)(*):與對照組比較逢顯著差異(P<〇.〇5)。 第25頁 1330533 五、發明說明(21) 【表5】 LCC細胞移植小鼠之血球數、血紅素量、及轉移集群數(n=7) 試驗删 正常組 對照組供試物組1 供試物組2 供試物(mg/Kg) 樣品1(100) 樣品1(300) 白血球數 (X l〇VL) 紐職 (X 104/^L) 血紅素量 (g/100mL) 肺臟中之艱 集群數(個) 3.65± 0.34 4.85± 0.30 4.08± 0.54 4.3〇± 0.79 η (*) (*) 782.0± 21.0 494.2± 30.4 631.5± 26.2 699.2+ 51.5 (*) (*) (*) 11.70± 1.09 6.93± 0.72 9.62± 0.43 10.51± 0.54 (*) (*) --- 21.5土 2.5 10.0ί 1.5 7.0土 1.0 (注)(*):與對照組比較達顯著差異(Ρ<〇·〇5)。 由表3數據得知移植L C C細胞之對照組(帶癌小鼠),其 腫瘤容積隨時間之經過而增大,但經口攝取供試物組(樣 品1 :含穀胺酸酐之巴西蘑菇萃取物)阻止(腫瘤容積)增 加,故LCC細胞之增殖顯然受抑制。 曰 由表4可知攝取供試物之結果腫瘤重量之增加明 抑制,除脾臟外各内臟之重量及最終體重在正常組、 Ϊ =二對/組:、及供試物投予組間未表現顯著差 、脾臟重里在對知、組為增加,但在供qmζ 增加(P < 0. 05達顯著差^^供式物投予組則抑制 抑制LCC細胞增殖之根據。 诹取供忒物(樣。〇1)
第26頁 1330533 五、發明說明(22) 由表5數據可知對照組白血球數較正 供試物投予組之間未達顯著差異。紅血球數/ ’但直、 增加(p<〇.〇5),證明經口投予巴西m物投予組則顯著 1使貝血狀態大約恢復正常。又供試物投予組 之LCC細胞轉移集群數與對照組比 攝取含穀胺酸針之巴西蘑蒜萃取物;择頁咸卜得知經σ 轉移。 曆姑卒取物(樣品1)抑制癌細胞之 試驗例3 與本發明有關之樣品,用以下方法試驗 :功^影響。亦即’由試驗例2摘取之脾臟分離脾細 該脾細胞於淋巴球分離液(大曰本製藥股份有限 二I缺1Γ.淋巴球分離溶液」),以20 0 0rpm遠心分離30分 鈿分,彳于淋I球。混存之紅血球以低滲透壓溶液處理去 除。,、次计异淋巴球數,調整至丨x i 〇6細胞數/丨〇 〇 # L,加 1。〇 # L「各種細胞表面抗原抗體(大日本製藥股份有限公司製 CD4「、抗小鼠、FITC標識」、「CD8、抗小鼠、FITC 才示識/」、「NK1. 1 '抗小鼠、R-PE標識」),於4。(:反應30 仝鉍後用磷酸緩衝液(日本和光純藥股份有限公司製品、 生物化學分析用試藥)洗清2次,加該磷酸緩衝液使成 +lmL ’用流動細胞計數法(Flow cytometry)測定CD4+、CD8 及NK1 · 1+之τ細胞數。結果如表6所示。 1330533 五、發明說明(23) 【表6】 汶 iNiU.rZ T 釉胞敷(n=7) 供試物組1 供試物組2 試驗誦 供試物(mg/Kg) 脾臟淋巴球數及CD4+、CD8+、 正常組 對照組 淋巴球數 (*) (*) (X 1〇7/脾臓) CDM細願 3.6肚 0.34 (*) 1,23± 0.20 3.15± 0.41 (X 1〇6/脾臟) 6.0± 1.5 2.0+ 0.5 3.5± 1.0 CDsnr細胞數 (*) (*) (X 1〇6/脾臟) 8.1+ 1.0 3.5+ 0.6 6.7+ 0.7 NKl.ll細胞數 (X 1〇ν脾臟) 2.0± 0.5 2.0± 0.3 (*) 4.5± 0.5 (注)(*):興對照組比較蓮顯著差異(p<〇.〇5)。 凑品1(100) 樣品1(3爾 η 2.98± 0.90 η 5.5± 1.0 (*) 6.5± 1.0 (*) 3.5± 0.5 由表6數據可知對照組(帶癌小鼠)之脾臟中淋巴 較正常組顯著減少,但在供試物投予組 淋球 脾踺中之CD4+ 丁細胞與CD8+ Τ細胞,對昭相★ 7^ 又 著減少,但攝取供試物(樣品η之結果抑制: = 之減少,而ΝΚ1·Γ Τ、細胞數則表現增 :兩種上 經口攝取含穀胺酸野之巴西蘑兹萃取物可=等見解二知 實施例6 a強免疫功犯。 由樣品1.:烏龍茶葉粉:2(重量此 之血管形成抑制用組成物5. 0K愈化工 組成之本發明 我粉(日本松谷化學
1330533
股份有限公司製品、商品名:巴印孚羅)3 · 5Kg、碟駿一 鈣0. 3Kg、維生素B! 0. 3Kg、維生素B20. 2Kg、維生素b 〜 0 · 2 K g、及維生素C 0. 5 K g —同裝入混合機搜拌混合j 〇八 鐘。該混合物供給直打式壓片機製成直徑7mm、高4mm、 量15〇mg小片後’用塗覆機塗覆蟲膠薄膜試作錠劑形狀^ 見。 v 食 實施例7 取牛油110g、鬆脆油(shortening)ll〇g、上等白 9〇g、及牛奶100mL裝入家庭用攪拌器,在搜拌下加雞轉 個充分混合後’與低筋麵粉19Og、發粉2g同時添加由蛋1 2及樣品3之混合物(3 : 1、重量比)組成之本發明之 形成抑制用組成物1 0 g充分混合。放置3 〇分鐘後用金屬言 具切割成5 0個,用烤箱烘烤試作奶油小餅乾。 模 實施例8 對市售蔬菜汁1L混合由樣品1 :樣品2 :葡萄種子#取 物(因他黑爾斯公司製品、商品名:阿克帝賓)=j : 2 . 1 (重量比)組成之本發明之血管形成抑制劑5g ,試作擔心 惡性腫瘤、關節風濕病人士用血管形成抑制用蔬菜汁。此 蔬菜汁與原來之蔬菜汁比較無任何遜色。 實施例9 樣品3 /樣品5==1/1(重量比)之混合物130mg、蜂膠 90mg、蜜臘I5mg、及玉米油15mg在4〇°C加溫下充分混合成 均勻液狀物。此液狀物供給勝囊填充機試作每顆内容量為 25Omg之明膠塗覆膠囊製劑。此製劑可利用為當做可能經
1330533 五、發明說明(25) 口攝取之食用組成物(飲食品)或醫藥用組成物(醫藥品)。 實施例1 0 粗碎巴西蘑菇(Agaricus blazei Murill)之乾燥子實 體’加氣仿/甲醇=1/1混合液加熱至50 r進行萃取處理 1小時,得氣仿/甲醇=1/1萃取物。加甲醇於該萃取物 以去除含甘露糖醇之甲醇不溶物調製甲醇可溶部,再加己 烷於此曱醇可溶部提取己烷不溶部(樣品6)。其次供己烷 不溶部於石夕膠管柱色層分析(silanised Silicagel60(石夕 烷化矽膠60) PF 25 4 : Merck 775 1、伊默克公司製品,提 取液水/ ·曱醇=7/ 3 ),調製茚滿三酮(n i nhy d r i η )陽性 反應部份(No.5、6分部)》其次供該分部於HPLC(Shimadzu LC-8A 系統:Shimpak PREP-ODS(M)、管柱:Φ 20 x 250mm、ShimadzuC日本島津製作所製品)、RT 6ml/min、 水/甲醇=5 / 1 ),調製茚滿三酮陽性反應部份(R t = 6〜 12min)。再供該分部於HPLC(Shimadzu LC-8A 系統: Shimpak PREP-ODS(M)、管柱:§ 20 x 250mm、
Shimadzu(日本島津製作所製品)、RT 6ml/min、水),調 製茚滿三酮陽性反應部份(Rt =8〜22min)。此茚滿三酮陽 性反應分部再以 TLC (Silicagel60 PF254 : Merck 7747、 伊默克公司製品,水/曱醇=1 /1 〇 〇 )精製,確認含有以 下物質。 亦即,以TLC (Silicagel 60 、Precoat TLC :Merck 5 715、伊默克公司製品’水/甲醇=1 /1 〇 〇)分析結果’ 確認丙胺酸(R f = 〇 . 2 7附近、茚滿三酿1陽性)、脯胺酸(R f
第30頁 1330533 五、發明說明(26) = 0.20附近、茚滿三酮陽性)、r胺基丁酸(Rf=〇. 15附 近、茚滿三酮陽性)、及不明物質(r f = 〇 · 4 〇附近、茚滿三 酮陰性)以4 9 : 5 : 2 5 : 21 (重量比)之比例存在。其次,將 該不明物質以NMR譜分析(裝置:Varian Unity Inova 500)及質譜分析(裝置:曰本曰立製作所股份有限公司製 品、M-4000H)結果得1H-NMR ((5. ppm, D20): 2. 09, 2.39(均 1H,m,H-3),2. 50(2H, m,H-4),4. 2 2( 1H,dd,J = 5. 2 及 9.0Hz);13C-NMR(<5 ppm, D20):184([00H 或-C=0-)、 182(-C=0-) '57C-CH-) ' 32(-〇 = C-CH2-) '28(-CH2-CH2 -);質譜(m/z) :42、84、及 129U+)。又旋光色散(〇rd) 分析(裝置:日本分光股份有限公司製品、ORD/UV-820 )之 結果為〔a〕D23-l 1. 5。(c =2、H20)。由此等分析結果, 鑑定上述不明物質為L-焦穀胺酸》 實施例11 使用10L容量培養裝置,以含葡萄糖5重量%、酵母萃 取物0. 5重量%、聚鰊(p〇lypept〇ne)l. 5重量°/。之培養 基,於26°C、通氣(2 vvm)、攪拌(I50rpm)狀態下培養裂 蹄木層孔菌之菌種培養液(1L)7日採取得菌絲體(200g)。 此菌絲體經乾燥及粉碎處理成菌絲體粉末,加己烷/乙 醇/水=3/4/1混合溶劑於40°C進行萃取處理30分鐘得可 溶物(樣品7)。該可溶物再以乙醇分級處理調製乙醇可溶 部’以己烷分級處理該乙醇可溶部調製己烷不溶部。其 次’與實施例1 〇相同以矽膠管柱層析、HPLC、TLC進行示
第31頁 1330533
五、發明說明(27) 差、精製處理,由質譜分析及NMR分析結果確認L_焦穀胺 酸之存在。 實施例1 2 依常法調製L-焦縠胺酸鈉。亦即,裝入重量% ^―焦 榖胺酸水溶液於附有搜拌器之燒瓶,於室溫緩緩攪拌下添 加0. 5N氫氧化鈉水溶液至pH無變化為止,其次經鹽析處理 後乾燥得L-焦穀胺酸鈉(樣品8)。 實施例1 3 於貫施例3,除原料L -榖胺酸以d l _榖胺酸代替外餘均 相同處理’調製成DL-穀胺酸鈉(樣品9)。 實施例1 4 粗碎巴西蘑菇之乾燥子實體加水,以常法於8〇〜95 β(: 進行熱水萃取處理’將該萃取液在減壓下乾燥處理調製巴 西蘑菇熱水萃取物’對該萃取物之40重量%水溶液加3倍 (重量)乙醇混合後’採取乙醇液層,減壓乾燥調製得乙醇 可溶物’將該可溶物以5倍(重量)己烷洗清後減壓乾燥調 製得己烷不溶物(樣品1 〇 )。 試驗例4 與本發明有關之焦穀胺酸、其衍生物、含此等之各種 加工處理物之血管形成抑制作用,依passaniti等之方法 (Laboratory Invest.,Vol. 67,P. 519〜528,1 992 ),由 MATRIGELTM 基質(matrix)(Becton Dikinson Labware 公司 製品、一種細胞培養基質、以下簡寫為MATR I GEL)所誘導 血管形成之程度調查之。
第32頁 1330533 五、發明說明(28) 亦即’ 5週齡C57BL/6雌性小(白)鼠(由日本查利斯利 巴股份有限公司購入)經1週之預備飼養後,選用健全小鼠 (1組5隻)’將下示供試物各〇. 5ml在冷卻下移植上述小鼠 腹部皮下’移植後第6日取出MATRIGEL觀察血管形成狀 態》又,將MATRIGEL冷凍乾燥後測定重量。再者,將取出 之MATRIGEL加純水lml後用p〇iytron均質器磨碎、2000rpm 遠心分離5分鐘後,其上清液以〇. 2 β ^過濾膜過濾,用血 紅素檢測-和光1^ (日本和光純藥股份有限公司製品)測定血 紅素量。
•正常組:MATRIGEL •對知、組· MATR I GEL +肝素(6 4單位)+酸性纖維芽細胞 增殖因子(以下簡寫為a_FGF)(1 ng/ml) •供試物添加組1 :對照組之組成物+樣品8 ( 8 0 0 η g/m 1) •供試物添加組2 :對照組之組成物+樣品8(4〇〇 g/m 1 ) •供試物添加組3 :對照組之組成物+樣品8(2〇〇 g/m 1 ) •供試物添加組4 :對照組之組成物+樣品9 ( 8 0 0以 g/m 1 ) •供試物添加組5 :對照組之組成物+樣品6 ( 6 〇 〇 g/m 1 ) •供试物添加組6 :對照組之組成物+樣品7 ( 8 0 0以 g/m 1)
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• 供試物添加組7 2〇〇 yczg/ml) • 供試物添加組8 g/m 1) • 供试物添加組9 g/m 1 ) 對照組之組成物+樣品6及樣品8 (各 對照組之組成物+樣品丨〇 ( 6〇〇以 對照組之組成物+比較樣品1 (800 v 试驗結果示如矣7。 π m主 各表中之數值以n=5、平均值土 由各表得知對照組較正常組顯著促進血管 重量“紅素量均增加。相較於此,於: ° 、加,,且,,樣品8 ( L-焦穀胺酸鹽)以濃产仿紹Mfc h 4丨、 MATR丨GEL重量及血紅素量之辦 ^晨度依賴性抑制 而樣品9m-焦穀胺酸鹽)雖^樣品;^;可抑制血管形成, 之抑制血管形成作用。又、樣〇 低’但亦確認相同 物)、樣品7(裂蹄木層孔菌萃“ 萃取物精製 管形成效果。又比較樣品1(巴西』::知具有強大抑制血 血管形成效果則小。又’就丙胺酸、脯f勿)之抑制 酸亦進行相同之有無阻止血管胺駄、及r胺基丁 均未表現阻止血管形成作用。 武驗,但此等物質 1330533 五、發明說明(30) 【表Ή MATRIGEL(划之重量及血紅素量(η=5) 試驗組別 供試物質 (添加量:/zg/ml) MATRIGEL 血紅素量 重量(me) (mg/MATRIGEL) 正常組 100.0± 12.1 5.3± 1.7 對照組 393.6± 22.7 33.0± 3.4 供試物添加組1樣品8 (800) 供試物添加組2樣品8 (400) 供試物添加組3樣品8 (200) 供試物添加組4樣品9 (800) 供試物添加組5樣品6 (600) 供試物添加組6樣品7 (800) 供試物添加組7樣品6(200) + 樣品 8 (200) 供試物添加組8樣品10 (600) 供試物添加組9比較樣品1 (800) 121.5± 28.1 4.8± 1.2 190.2± 30.4 17.5± 3.6 265.3± 18.6 23.4± 2.0 209.0± 30.8 15.8± 2.7 110.7± 10.3 4.0± 0.5 136.4± 24.5 6.1± 2.4 150.5± 23.1 8.3± 1.8 154.1± 27.2 9.0± 4.3 320.4+ 35.2 30.5± 4.5 ※ MATRIGEL™(Becton Dikinson Labware 公司製品)matrix 試驗例5 與本發明有關之樣品,用以下方法試驗並評估其抑制 腫瘤增殖作用及抑制腫瘤轉移作用。亦即,由日本理化學 研究所受讓之路易士肺癌(以下簡寫為LLC)細胞懸浮於磷 酸.生理食鹽缓衝液〇!17.4)。另一方面,6週齡0 5731^/61 雌性小鼠(由日本克雷亞股份有限公司購入)經1週之預備 飼養後,取健全小鼠(1組8隻)在戊巴比多鈉麻醉下進行小 切開,對露出之脾臟注入LLC細胞懸浮液(LLC細胞數1 · 0 X 1 05)後,立即缝合小切開。移植LLC細胞1 2小時後,經口铁 予蘑茹萃取物(樣品6)100 mg/kg(體重)或3 0 0 mg/kg(體
1330533 五、發明說明(31) 重)、1日1次、連續30日。正常組及對照組(LCC帶癌小鼠) 則投予蒸鶴水以代替樣品6。於此試驗期間,癌細胞增殖 率以每隔3〜5日測定癌組織容積量(用長徑X短徑2/2)計 算°在癌細胞移植後第31曰將各組小鼠在乙醚麻醉下,由 靜脈以加肝素採血,用血細胞庫爾特計數器(c〇ulter counter)測定血中之白血球數、紅血球數、及血紅素量; 另外,宰殺採血後之小鼠,摘取癌組織、肝臟、肺、脾臟 及胸腺,測定各組織之重量;並以立體顯微鏡計算轉移肺 組織之癌鈿胞集群數。 LCC細胞移植小鼠之腫瘤組織容積量,癌組織及各臟 器之重量,·白血球數、紅血球數、血紅素量、及肺轉移集 群數分別列如表3、表4、表5。又各表令數值以平均值士 標準誤差表不’顯者性測驗以費雪保護最低效數位測驗 (Fisher’s Protect LSD Test)進行,並 ϋζρ <〇.〇5為差異 顯著。 、 【表8】 umm\ LCC細胞移植小鼠之腫瘤容積量(η=8) 對照組 供試物組1 供試物(mg/Kg) 腫瘤容積量(mm3) 移植後7日 12曰 17曰 21曰 24曰 30曰 405+ 40 617± 84 806± 137 1430± 280 1916± 325 2190± 382 樣品6(100) 285± 72 310土 94(*) 552± 108 503± 131(, 745;± 186(*) 1067± 292(*) ^供試物組2 壤品 6(300) 182± 31(*) 244土 83(*) 317士 105(*) 416土 122(*) 503土 169(*) 670+ 213(*)
(注)(*):與對照組比較緯顯著差異(P<〇.〇5)
第36頁 1330533 五、發明說明(32) 【表9】 LCC細胞移植小鼠之纖重量(η=8) 試驗_ 正常組 對照組 供試物組1 供試物組2 供試物(mg/Kg) 樣品6(100) 樣品6(300) 起始體重(g) 18.5±0.25 18.3 土 0.34 18.5±0.26 18.2±0.22 最終體重(g) 21.4±0.36 23.1±0.54 21.6±0.87 22.1+0.43 腫瘤雷量(m2) — 3061±785 745±403 4801130 脾臟(g) 0.08±0.02* 1.43±0.07 0.81±0.10* 0.45±0.03* 肝臟(g) 1.21±0.05 1.39±0.10 1.25±0.05 1.22±0.04 肺(mg) 164.8±7.1 187.7±15.2 184.4±13.1 175.0±5.2 胸腺(mg) 58.5±3.9 46.8±6.6 47.9±4.9 51.5+5.0 (注)* :與對照組比較達顯著差異(Ρ< 0.05)。
第37頁 1330533 五、發明說明(33) 【表10】 LCC細胞移植小鼠之血職、血紅素量' 及轉移集群數(n=8) 試驗組別 正常組 對照組供試物組1 供試物組2 供試物(mg/Kg) 樣品1(100) 樣品1(300) 白血職 (x108//zL) 紅血職 (x104/#L) 血紅素量 (g/100mL) 肺臟中之_ 集群數(個) 3.32±0.18 5.73±1.40(*1) 4.72±1.13 4.1210.59 799.0±7.4(*) 506.3±78.4 692.6±37.2(*) 743.2±22.0(*) 12.4±0.09(*) 7.80±1.25 10.6±0.59(*) 11.3±0.39(*) --- 30.0±2.8 15.8±2.5(*) 13.6+1.4(*) (注)* :與對照組比較達顯著差異(P< 0.05)。 * 1 :與正常組比較達顯著差異(P< 0.05)。 由表8數據得知移植LCC細胞之對照組(帶癌小鼠),其 腫瘤容積隨時間之經過而增大,但經口攝取供試物組(樣 品6 :含焦穀胺酸之巴西蘑菇萃取物)阻止(腫瘤容積)增 加,故LCC細胞之增殖顯然受抑制。 由表9可知攝取供試物之結果腫瘤重量之增加明顯被 抑制,除最終體重及脾臟外各内臟之重量在正常組、LCC 細胞移植組(對照組)、及供試物投予組間未表現顯著差
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異。脾臟重1在對照組為增& ’但在供試物投予 增加(P <0· 05達顯著差異),得知經口攝取供試物(品^ 抑制LCC細胞增殖之根據》 、 ’ 由表1〇數據可知對照組白血球數顯著較正常組增加, :與供試物投予組之間未達顯著“。红血球㈣血紅素 =對照組顯著減少而呈貧血狀態,但在供試物投予組則 =Γ:力要::。·05),證明經口投予巴西蘑兹萃取物(樣品 6^果使貝血狀態大約恢復正常。又供試物投予組之 臟中之LCC細胞轉移集群數與對照組比較顯著減少,得知 經口攝取含焦縠胺酸之巴西蘑菇萃取物(樣品6)抑制癌細 胞之轉移。 試驗例6 與本發明有關之樣品,用以下方法試驗並評估其對免 疫功能^影響。亦即,由試驗例5摘取之脾臟分離脾細 胞’重豐该脾細胞於淋巴球分離液(大日本製藥股份有限 公司製品「淋巴球分離溶液」)’以2 〇 〇 〇 Γρπ]遠心分離3 〇分 鐘分離得淋巴球。混存之紅血球以低滲透壓溶液處理去 除。其次計算淋巴球數,調整至1 X 1 〇6細胞數/ i 〇 〇 V L,加 1 0 M L各種細胞表面抗原抗體(大日本製藥股份有限公司製 品之「CD4、抗小鼠、fitC標識」、「CD8、抗小鼠、FITC 標識」、「NKl. 1、抗小鼠' R-pe標識」),於4。(:反應30 分鐘後用碟醆緩衝液(日本和光純藥股份有限公司製品、 生物化學分析用試藥)洗清2次,加該磷酸緩衝液使成 lmL,用流動細胞計數法(Flow cytometry)測定CD4+、CD8
第39頁 1330533 五、發明說明(35) +、及NK1. Γ之T細胞數。結果如表11所示。 【表11】 脾臟淋巴球數及CD4+、CD8+、及NK1.1+之T細胞數(n=8) 試驗麵 正常組 對照組 供試物組1 供試物組2 供試物(mg/Kg) 樣品6(100) 樣品6(300) 淋巴球數 (X107/脾臟) CD4+T細胞數 3.52±0.48(*) 1.47±0.22 2.84±0.36(*) 3.01±0.45(*) (xlO6/脾臟) CD8+T細胞數 6.5±0.8(*) 2.1±0.4 4.6±0.5(*) 6.0±1.1(*) (xlO6/脾臟) ΝΚ1.1+Τ細胞數 7.7±1.2(*) 4.5±0.7 6.6±0.6(*) 8.9±0.8(*) (xlO5/脾臟) 1.7±〇.2(*) 2.610.3 2.8±0.3(*) 4.0±0.5(*) (注)* :與對照組比較達顯著差異(Ρ< 〇.05) 〇 由表1 1數據可知對照組(帶癌小鼠)之脾臟中淋巴球數 較正常組顯著減少,但在供試物投予組則抑制此減少。 又’脾臟中之CD4+ τ細胞與CD8+ τ細胞,對照組亦較正常 組顯著減少,但攝取供試物(樣品6)之結果阻止該兩種細 ,數之減少,而NK1. 1+ τ細胞數則表現增加。由此等見解 侍知經口攝取含穀胺酸酐之巴西蘑菇萃取物可增強免疫功 能。 實施例1 5
第40頁 1330533 由樣品1 〇 : l独# 0 . , θ , 馬龍I葉粉:番石榴葉熱水萃取物=3 : 2 · 1 (重置比)έθ 4、λ«丄 ιη ni/ t 、·且成之本發明之血管形成抑制用組成物 lO.OKg與化工嫩#、r „ ^ 敎私(日本松谷化學股份有限公司製品、商 口口名·巴印孚、7 Λ r, n ,T/ 、准)7. 〇Kg、磷酸三鈣0. 5Kg、維生素B,
0.4Kg、維生幸R 東〇. 4Kg、維生素β6 〇. 5Kg、及維生素〇 j 2 g—同裝入昆合機攪拌混合ι〇分鐘。該混合物供給直打· 片機製成直把7mm、高4mm、重量1 50mg小片後,用塗 f ’塗覆蟲膠薄膜試作錠劑形狀食品。此錠劑可利用於提 咼體内免疫力,及糖尿病或癌等生活習慣病之預物為目 的0 實施例1 6 取牛油120g、鬆脆油(shortening)100g、上等白糖 l〇〇g、及牛奶l〇〇mL裝入家庭用攪拌器,在攪拌下加雞蛋工 個充分混合後,與低筋麵粉20 0g、發粉2g同時添加由樣。 6 .樣品7 :樣品8 =2 : 2 : 1 (重量比)混合物組成之本發: 之血管形成抑制用組成物3 0 g充分混合《放置3 〇分鐘後 金屬模具切割成50個,用烤箱烘烤試作奶油小餅刀乾里/用 實施例1 7 ^ 對市售蔬菜汁1 L混合由樣品8 :樣品丨〇 :葡萄種子— 取物(因他黑爾斯公司製品、商品名:「阿克帝賓)一萃 1 :2 :1(重量比)組成之本發明之血管形成抑制劑/ 了 作防止體内組織氧化,惡性腫瘤 '關節風濕病、糖 ^ 預防用蔬菜汁。此蔬菜汁與當做原料之蔬菜汁比較其=
Γ330533 五、發明說明(37) 實施例1 8 樣品6 /樣品10 =1/丨(重量比)之混合物i〇〇Kg、銀杏葉 萃取物20Kg、鯊魚軟骨萃取物30Kg、蜜臘10Kg、及玉米油 140Kg比例之原料在8〇它加溫下充分混合成均勻液狀物。 此物供給膠囊填充機試作每顆内容量為25〇mg之明膠塗覆 膠囊製劑。此製劑可利用為當做可能經口攝取之食用組成 物(飲食品)或醫藥用組成物(醫藥品)。 [發明效果] 依本發明可提供含有榖胺酸酐及/或其衍生物、或焦 穀胺酸及/或其衍生物為有效成分之血管形成阻止用組成 物。在此’榖胺酸酐或焦穀胺酸為L型,穀胺酸酐衍生物 或焦穀胺酸衍生物為鹽或醯胺,穀胺酸酐及/或其衍生 物、或焦榖胺酸及/或其衍生物為化學合成物’巴西蘑 蒜、裂蹄木層孔菌等擔子菌類子實體或菌絲體所得萃取物 時’表現更顯著之血管形成阻止效果。又,依據本發明, 尤其由焦穀胺酸及/或其衍生物組成之上述血管形成阻止 用組成物確認其抗腫瘤作用及免疫活化作用’而提供抗腫 瘤作用及免疫活化作用組成物。該組成物可利用為增強生 體免疫功能及治療或預防血管形成為病因之各種疾病之醫 藥品、飲食品等。
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US (1) | US7977379B2 (zh) |
KR (1) | KR100971599B1 (zh) |
TW (1) | TWI330533B (zh) |
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-
2003
- 2003-05-15 TW TW092113214A patent/TWI330533B/zh not_active IP Right Cessation
- 2003-05-15 US US10/439,020 patent/US7977379B2/en not_active Expired - Fee Related
- 2003-05-15 KR KR1020030030801A patent/KR100971599B1/ko not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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TW200306789A (en) | 2003-12-01 |
US7977379B2 (en) | 2011-07-12 |
KR20030095228A (ko) | 2003-12-18 |
US20040029955A1 (en) | 2004-02-12 |
KR100971599B1 (ko) | 2010-07-20 |
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