TWI279231B - Neutralization agent of vacuolization toxin - Google Patents
Neutralization agent of vacuolization toxin Download PDFInfo
- Publication number
- TWI279231B TWI279231B TW093129616A TW93129616A TWI279231B TW I279231 B TWI279231 B TW I279231B TW 093129616 A TW093129616 A TW 093129616A TW 93129616 A TW93129616 A TW 93129616A TW I279231 B TWI279231 B TW I279231B
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- toxin
- proanthocyanidins
- helicobacter pylori
- agent
- cytosine
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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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
- A61K31/33—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
- A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Description
1279231 九、發明說明: 【發明所屬之技術領域】 本發明是有關於具有可使幽門螺旋菌所產生之空胞化毒 素無毒化之效果之前花青素類,特別是有關於含有得自蘋果、 5 或忽布花之前花青素類作為有效成分以進行幽門螺旋菌相關 消化器官疾病之預防、預防復發或治療之醫藥品、醫藥部外品 及飲食品,以及幽門螺旋菌所產生之空胞化毒素之中和劑、醫 藥品、醫藥部外品及飲食品。 【先前技術】 10 忽布花是桑科蛇麻草屬多年生植物,其毯花(成熟之未授 精雌花)一般稱為忽布花。忽布花除了其花部之外,還有葉、 蔓、根等各部位。存在於忽布花毯花中之忽布素部分(形成於 毯果之内苞之根部之黃色顆粒)是忽布花之苦味、芳香之本 體,在啤酒之釀造上,與酵母、麥芽並列而為重要之啤酒原料。 15 又,忽布花在民間療法中通用為鎮靜劑或抗催淫劑。忽布花苞 係從忽布毯花除去忽布素部分者,對啤酒釀造並無用處,有時 彳見情況在釀造啤酒時去除,而生成為副產物。這時,急布花苞 除了作為土壤改良用之肥料外,尚未發現有其他特別有效之利 符法,因此期待能開發出附加價值更高之利用法。 2Q 又,在與本申請人之申請案有關之專利文獻1、2、3、4、 $、6中,確認了關於來自於忽布花、尤其是忽布花苞之聚酚類 具有抗氧化作用、對發泡麥芽飲料之泡沫安定化作用、抗腐蝕 作用、消臭作用、抑制癌細胞轉移作用、去氧核糖核酸拓樸異 構酶(DNA-Topoisomerase)阻礙作用。又,專利文獻7中, 1279231 確認了其具有用財和RNΑ Ν·_ m或adp核糖酶化 轉移崎(ADP-ribosyltransferase )活性所具蛋白質毒素之六文果 然而,關於來自忽布花之前花青素類,目前為止並未有任= 子明白揭示其具有可用以將幽門螺旋8所產生之空胞化毒素 5 中和(無毒化)之效果。 ” 幽門螺旋菌是具有螺旋形態之革蘭氏陰菌,自從瓦連及馬 歇爾報告其存在(非專利文獻υ以來,已明瞭其與急性胃炎、 慢性胃炎、胃«、十二彳旨腸賴㈣化狀發病有著 密切關聯(參考非專利文獻2、3、4)。又,從幫以上之胃癌 10 15 病患是幽門螺旋菌之帶菌者這點來看,幽門螺旋菌與發生胃癌 有關如之可祕报高,簡〇在1994年甚至發表「幽巧螺旋菌 無疑是胃癌之致癌因子」。 幽門螺旋菌所產生之病因因子,目前為止報告的有尿素 酶過氧化氫分解崎、脂多糖(Lps)等,近年,在胃之黏膜 細胞上單獨投予可引起空胞化變性之空胞化毒素(VacA),結 果在動物拉式身上證實其引起胃炎(非專利文獻5),因此,對 马幽門螺旋菌之主要病因因子的認識急速增加 /後針對胃潰瘍、十二指腸潰瘍等潰瘍性疾病之 療,係使用索法_、並 ,» g勞諾托等抗潰瘍劑;奥美拉唑、蘭索 唑4質子幫浦抑制劑 (PPI);法模替丁、析米替丁等胃酸分 抑制劑(H2阻斷劑) 寺。然而,這些藥物並不具有抑制幽門: 方疋鹵增殖之效果, 疋叶對潰瘍性疾病之對症療法劑。因此 即使藉上述藥劑治齋 〜、喝居性疾病,但由於幽門嫘旋菌仍然殘; 體内,故在治療結束後1年以内之復發率高達80肩%, 20 1279231 為了克服上述缺點,除了對症療法之外,另外還有將幽門 螺旋菌除菌之治療法,亦即,於臨床上使用對幽門螺旋菌具有 抗菌效果之阿莫西林、克拉黴素、硝基嘧唑乙醇、替硝唑等抗 生素。現在,組合正子幫浦阻斷劑與抗生素2劑,亦即所謂新 5 3劑併用療法是除菌治療之主流。 然而,新3劑併用療法在比較上必須長期大量投藥,因此 現實上產生了諸如藥劑副作用或微生物交替之發病這些臨床 上的問題。又,抗生素之使用,可能會隨著菌體之破壞,使幽 門螺旋菌所產生之病因因子之空胞化毒素在胃黏膜周邊大量 10 排出。又,抗生素之大量使用恐怕會導致新穎而且更頑強之耐 性菌產生。綜合以上知識,現在廣為使用之新3劑併用療法也 很難算是理想的治療方法。 ;: 在日本,幽門螺旋菌之感染在40歲以上之世代尤其高, 而且,潰瘍性疾病、及胃癌之發病率也較歐美為高,若能找出 15 沒有副作用或耐菌性問題之治療法,在產業上的價值是很大 ; ;,; . · 【專利文獻1】特開平09-002917號公報 【專利文獻2】特開平09-163969號公報 【專利文獻3】特開平09-295944號公報 ' ' .· i : - 20 【專利文獻4】特開平1〇-〇25232號公報 【專利文獻5】特開平2000-327582號公報 【專利文獻6】特開平2001-039886號公報 【專利文獻7】國際公開第02/07826號冊 【非專利文獻 1】Lancet,1273-1275,( 1983) 1279231 【非專利文獻 2】Med.J.Aust·,142,436 ( 1985) 【非專利文獻 3】Gastroenterology, 102,1575 ( 1992) 【非專利文獻 4】N.Engl.Med·,328,308 ( 1993) 【非專利文獻 5】Infect. Immun_63,4154-4160 ( 1995) 5【發明内容】 因此,本發明之目的是提供副作用少、無耐性菌發生、對 幽門螺旋菌相關消化器官疾病之預防、預防復發或治療、及對 幽門螺旋菌所產生之空胞化毒素具有中和效果之醫藥品、醫藥 部外品、飲食品。 10 本發明人鑒於上述現狀,因此試著以找出使幽門螺旋菌所 產生之空胞化毒素無毒化之因子來解決問題,而不是使幽門螺 旋菌死滅。若找出空胞化毒素之效果性無毒化因子,則在醫 學、產業上之意義是無可計測的。 本發明人再三研討之結果,發現存在於忽布花及蘋果中之 15 聚紛之一種,可有效使幽門螺旋菌所產生之空胞化毒素無毒 化,因而完成了本發明。蘋果之未熟果或忽布花之苞部分尤其 大量含有該聚酚。忽布花中所含之該聚酚會吸附在苯乙烯-二乙 稀苯樹脂等與聚驗顯示出親和性之樹脂,且在藉離析分子量 1,000以上之超濾膜處理時,具有不透過膜之性質,甚至在含 20 有5%鹽酸之醇溶液中加熱時,會被水解而產生花青素,因此 判斷其為前花青素類。又,該前花青素類在GPC (膠質透過色 層分析)分析中,給予如第1圖之色層譜,另一方面,在消光 度分析中,給予如第2圖之消光度分布。 又,蘋果中所含該聚酚也會吸附在苯乙烯-二乙烯苯樹脂等 1279231 與聚酚顯示出親和性之樹脂,且在含有5%鹽酸之醇溶液中加 熱盼,會被水解而產生花青素,因此判斷其為前花青素類。 亦即,本發明是有關於含有前花青素類、尤其是含有來自 w布化或絲之前花青素類為有效成分之空胞化毒素中和劑。 作為中和空胞化毒素之物質,5-硝基·2- (3·苯基丙胺基) 笨酉夂或根皮素、甚至部份聚紛類,可抑制藉空胞化毒素所生成
胞I、上之電W變化,這點已由指出(τ⑽F al·,FEBS Lett.543,l84_189 ( 2〇〇3 ))。然而,該相同文獻中也敘 述,這些系統中之抑制細胞膜上電流變化之物質,與阻礙空胞 10化毋素所導致之細胞内空胞化、或中和細胞毒性並無關係。 又乂二文獻中所揭不之作為抑制細胞膜上電流變化之物質之 化合物,雖然是聚盼類,但全都不是前花青素類之化合物。 因此,利用來自於植物、尤其是來自於忽布花或頻果之前 花青素類使空胞化毒素無毒化之技術,目前為止完全沒有任何 15 報告。 發明效果 本發明之线化毒素巾㈣具有使㈣化毒素無毒化之 效果,因此在預防及治療以空胞化毒素為病原因子之感染症上 是有效的。本發明品可作為以空胞化毒素為病原因子之感染症 2〇之預防说療劑、及生化學性實驗用試劑等並將之製品化。 幽門螺旋菌相關之消化器官疾病可舉胃潰癌、十二指腸潰 瘍、胃炎、胃癌、MALT淋巴瘤等。 【實施方式】 本發明之空胞化毒素中和劑之原料以蘋果之未熟果為 9 1279231 宜,此外還有忽布花之蔓或苞部分,尤其可不分離蘋果或忽布 花之各部分,而使用整體。 所謂忽布花苞,是指從忽布花毬果除去忽布素部分而得 者,一般而言,是在將忽布花毬果粉碎後,以篩揚除去忽布素 5 部分,藉此得到忽布花苞。然而,最近在啤酒釀造上,為了省 去將忽布花苞篩分出來除去之時間勞力,因此傾向於不除去在 釀造啤酒上無用之忽布花苞,而直接將忽布花毬果成形為小球 狀,以忽布花小球利用於啤酒釀造上。因此,本發明之原料只 要是包含忽布花之蔓或苞者即可,並無特別限定,以包含忽布 10 花苞之忽布花毬果或忽布花小球為原料也沒有問題。 從忽布花取得空胞化毒素中和劑時之製造方法,係以忽布 花蔓、苞、或含有忽布花苞之忽布花毬果或忽布花小球、或者 含有上述忽布花值物體之部分者為原料,將之以水或80v/v%以 下之醇、酮、乙腈等與水混合之有機溶劑之水溶液萃取。適當 15 之例子可舉乙醇50 v/v%以下之含水乙醇。原料與萃取溶劑之 比例以1 : 20〜100 (重量比)為佳,又,萃取係在4〜95°C、於 攪拌下進行20〜60分鐘。萃取液可藉過濾取得,不過若有必要 也可利用珠岩等過濾助材。 可從如此得到之萃取液以濃縮、冷凍乾燥、喷霧乾燥等一 20 般方法將溶劑除去,以粉末得到空胞化毒素中和劑。在此所得 到之空胞化毒素中和劑已可充分供於實用,而若有必要,亦可 藉下述利用吸附樹脂之方法進一步提高其精製度。唯,該過程 純粹是用以提高精製度之步驟,若無必要亦可省略。 藉由業已作成粒狀之與聚酚類具有親和性之合成樹脂來 10 1279231 處理上述萃取液,濃縮空胞化毒素中和劑。該步驟可採用使忽 布花萃取液通過充填有該粒狀合成樹脂之管柱中,將管柱充分 洗淨後’將吸附於管柱之空胞化毒素中和劑溶出之方法,亦可 將粒狀樹脂浸潰於忽布花萃取液,以批式處理來進行。 5 在使空胞化毒素吸附於合成樹脂時,在將忽布花萃取液冷 卻到15〜30°C之室溫後,可因應需要,藉減壓濃縮等事先降低 萃取液之有機溶劑濃度,以提高吸附效率。合成吸附劑之材質 可使用羥丙基化類糊精、親水性乙烯聚合物、苯乙烯_二乙烯苯 聚合物等。 〇 接著,可將合成樹脂洗淨,進一步提高空胞化毒素中和劑 之精製度。用於洗淨之溶劑以水乃至丨〜⑴〜/〜%之乙醇水溶液 為佳,而以使用樹脂量之丨〜仞倍之溶劑量進行洗淨為佳。 接者’從吸附聚齡類之合成樹脂將空胞化毒素中和劑脫離 溶出。用於溶出之溶劑可使用含水醇、含水酮、含水乙腈等, 尤其適當之例子可舉3〇 w/w%以上之乙醇水溶液或乙醇。溶出 洛劑之通液量以樹脂量之2〜6倍為佳。 藉濃縮、冷凍乾燥、喷霧乾燥等一般方法從所得到之溶出 夜除去心劑,以粉末得到空胞化毒素中和劑。又,在減壓濃縮 之際’可回收醇、鋼、乙腈等再利用。所使用之合成樹脂在經 過80 v/v%以上之醇水溶液、〇 〇5n之氮化納水溶液等洗淨後, 可重複使用。 如此知到之空胞化毒素中和劑可直接供於實用, 而亦可藉 利用如下逆之超濾膜之方法,更進一步提高其精製度。唯,該 過私純粹是用以提高精製度之步驟,若無必要亦可省略。 11 Π79231 5 10 15 20 將上迹方法獲得之空胞化毒素中和劑溶解於水、或與水混 合之有機溶劑,以離析分子量L000以上之超濾膜處理。膜之 素材可使用纖維素、乙醯纖維素、聚丙烯、聚酯、聚砜、聚醚 砜、PVD等一般作為超濾膜材質來使用者,並無特別限制。又, 離析分子量只要在1,〇〇〇以上即可使用,無特殊問題,不過芳 使用離析分子量過大之膜,則產率將大量下降,或離析分子量 k4則處理上所需時間變長,因此以離析分子量 ’000 50,000之超渡膜為佳。又,處理係視萃取溶劑之種類、 或萃取溶劑與忽布花或忽布花爸之比例而定,不過最好進行刻 上部殘液之量大約是處理開始時之·^觸為止。這時的壓 力係視超顏或過缝置而定,不過以大㈣H崎細2為 佳。又,若有必要,亦可將一度已處理完成之上部殘液再次以 水等適當溶劑稀釋,以同樣方法再處理以提高精製度。 。可將所得到之上部殘液之溶劑以濃縮、冷滚乾燥、喷霧乾 燥等除去,崎末得到空胞化毒素。又,在減壓濃縮 之際,可回收醇、_、乙腈等再利用。 此4于到之空胞化毒素中和劑是略呈苦味之無臭之膚 色、褐色乃至淡黃色之粉末,會吸附於與㈣具有親和性之合 成樹脂,而藉離析分子量以上之超_處理時並不透過 膜之前花青素。 又,產率方面,以忽布花乾重量換算時為〇 5〜2〇 〇w/w%, 以忽布花毬果重量換算時則為05〜150w/w%。 攸頻果取得空胞化毒素中和劑時之製造方法,係藉壓搾從 韻果果實、尤宜為蘋果未熟果搾汁,得到饱胞化毒素中和 12 1279231 劑之溶液,再將該溶液藉濃縮、冷凍乾燥、喷霧乾燥等一般方 法製成粉末來使用。又,可因應需要,利用充填有與聚酚類具 親和性之粒狀樹脂等管柱,將空胞化毒素中和劑進行精製以提 高精製度來使用。該步驟與得自忽布花之空胞化毒素中和劑之 5 濃縮精製步驟作業相同。 如此得到之空胞化毒素中和劑,可與一般所使用之載體、 助劑、添加劑等一起製劑化,依據常法以經口、非經口製品來 作為醫藥品使用,或混合於食品素材而作為飲食品。 醫藥品之經口劑有錠劑、膠囊劑、顆粒劑、糖漿劑等,而 10 非經口劑有軟膏劑、霜、水劑等外用劑,無菌溶液劑或懸濁劑 等注射劑等。將這些製品以醫藥投藥於人體時,係將 2mg~500mg之量以1日1至數次來投藥,亦即以全日量 2mg〜lOOOmg來投藥,即可充分奏效。 本發明之含有空胞化毒素中和劑之醫藥品,可與生理上認 15 可之媒介劑、載體、賦形劑、統合劑、安定劑、香味劑等取得 所要求之單位容量形態。混合於錠劑、膠囊劑之佐藥係如下 者。如西黃耆膠、金合歡膠、玉米澱粉、明膠之結合劑;如微 晶性纖維素之賦形劑;如玉米澱粉、全明膠化澱粉、精胺酸之 膨化劑;如硬脂酸鎂之滑澤劑;如蔗糖、乳糖、糖精之甘味劑; 20 如薄荷、紅珠樹油、櫻桃之香味劑等。又,膠囊劑之情況除上 述材料外還可含有如油脂之液體載體,又,其他材料可作成被 覆劑、或以其他方法來變化製劑之物理性形態。例如,錠劑可 以蟲膠、砂糖被覆。糖漿劑或酏劑可含有砂糖作為甘味劑、對 羥基苯曱酸曱酯或對羥基苯甲酸丙酯作為防腐劑、色素及櫻桃 1279231 或柳橙香味之香味劑。 來乍為庄㈣之無菌組成物’係可使如注射用水之載色 劑中之活性物質、如芝麻油、椰子油、落花生油、棉籽油之天 5 10 然產出板物油、或如油酸醋之合成樹脂載色劑溶解或懸浮之一 般方法來處方。又,— ’、可因應需要混合緩衝劑、防腐劑、 化劑等。外用劑可使用 一…凡士林、石臘、油脂類、含水羊脂、聚 乙-%寻為基材,藉_般方法作成好劑、霜劑等。 含有本發明⑽化毒素中和劑之飲食品可製成上述製劑 亦可以糖果、仙貝、餅乾、飲料等形態,於 料中添加需要量,藉—浐製、…… “原 #叙製造方法加工製造。作為健康食品、 “匕性食品來攝取時’係用以預防疾病、維持健康,因此可作 為日數-人經口攝取且全曰量含有5mg〜5〇〇mg之加工品來 取0 於這些飲食品中添加空胞化毒素中和劑時,可直接以粉末 15狀添加空胞化毒素中和劑,亦可將空胞化毒素中和劑作成卜㈣ 之切液或乙醇水溶液之溶液或乙醇溶液,添加於飲食品中, 使最終濃度相對於飲食品為^,麵觸,又以議〜5麵_ 為佳。 本發明之空胞化毒素中和劑,當以預防該消化器官疾病為 目^使狀際’則可作為預_來使用,若以預防曾經治癒 玄肩化☆•官疾病之復發為目的使用時,則可作為預防復發劑 來使用,而若以藉除去幽門螺旋菌來治療該消化器官疾病為目 的來使用之際,則可作為除菌劑來使用。又,在進行該消化器 官疾病之預防、預防復發或治療之際,可單獨使用本發明之幽 14 1279231 門螺旋菌除菌劑,亦可併用質子幫浦阻斷劑及/或抗生素。 本發明之空胞化毒素中和劑之一曰投藥量,可依據其用 去、患者年齡、性別及其他條件、疾病之程度等來適當選擇, 通常有效成分之本發明化合物之量為成人每1日O.^ZOOOmg, 5 又以〇·5〜1800mg為佳,而以i.〇~i5〇〇mg尤佳,可1日分1~4 次’在例如空腹時投藥。 以下,顯示實施例,不過本發明並不限定於這些實施例。 【實施例1】 (藉膠質型合成吸著劑之源自忽布花毬果之空胞化毒素 10中和劑之調製) 於缽中將忽布花毬果20g粉碎,並以2L之水擾拌,在該 授拌下於95°C進行40分鐘萃取。過濾、後放冷,使萃取液通過 業已充填有親水性乙烯聚合物樹脂80ml之管柱,接著以400ml 之5%乙醇水溶液洗淨,更使80%乙醇水溶液400ml通過相同 15 管柱,將該溶出液回收並冷凍乾燥,以無臭而略呈苦味之淡黃 色粉末得到空胞化毒素中和劑800mg。從忽布花之產率為4%。 【實施例2】 (藉膠質型合成吸著劑之源自忽布花苞之空胞化毒素中 和劑之調製) 20 以600ml之50%乙醇水溶液攪拌忽布花苞20g,攪拌同時 於30°C進行20分鐘萃取。過濾後減壓濃縮,,使該濃縮液通 過業已充填有苯乙烯-二乙烯苯樹脂80ml之管柱,接著以4〇〇ml 之水洗淨,更使80%乙醇水溶液400ml通過相同管柱,將該溶 出液回收並冷凍乾燥,以無臭而略呈苦味之淡黃色粉末得到空 15 1279231 胞化毒素中和劑1.6g。從忽布花苞之產率為8%。 【實施例3】 (藉超濾膜之源自忽布花毬果之空胞化毒素中和劑之調 製) 5 於缽中將忽布花毬果20g粉碎,並以2L之水攪拌,在該 攪拌下於95°C進行40分鐘萃取。過濾後放冷,藉離析分子量 50,000之超濾膜,在1.0kg/cm2、室溫下處理該抽出液,直到變 成20ml為止。將所得到之上殘液減壓乾涸,而以無臭而略呈 苦味之淡黃色粉末得到空胞化毒素中和劑200mg。從忽布花之 10 產率為1%。 【實施例4】 (藉超濾膜之源自忽布花苞之空胞化毒素中和劑之調製) 以600ml之50%乙醇水溶液攪拌忽布花苞20g,在該攪拌 下於80°C進行40分鐘萃取。過濾後,藉離析分子量1,000之 15 超濾膜,在3.Okg/cm2、室溫下處理該抽出液,直到變成60ml 為止。將所得到之上殘液冷凍乾燥,而以無臭而略呈苦味之淡 黃色粉末得到空胞化毒素中和劑〇.8g。從忽布花之產率為4%。 【實施例5】 (空胞化毒素中和劑之進一步精製及定性分析) 20 將實施例2中得到之空胞化毒素中和劑0_8g,溶解於500ml 之10%乙醇水溶液,並藉離析分子量5,000之超濾膜,在 1.Okg/cm2、室溫下處理直到變成20ml為止。將所得到之上殘 液冷凍乾燥,而以無臭而略呈苦味之肌肉色粉末得到空胞化毒 素中和劑0.4g。將該粉末藉下述所示之條件進行HPLC分析, 16 Ϊ279231 即成為特徵如第3圖所示之色層譜,又,進行一般性聚酚類定 里法之一之兒茶素定量(食品公定分析法)時,換算為兒茶素 含量得到40.6%之值。 (HPLC條件) 裝置:島津LC-10A系統、管柱·· ODS-80TM (東y—、 4_6mmI.D_x25cm)、移動相:從(a 液:B 液)=(1〇〇 : 〇)到 同(50 : 50)為止30分鐘之直線梯度、a液:5%乙腈(含 HC1) B液·乙腈、樣本注入量·· 2〇 # g、檢出:在2〇〇〜3〇〇nm 檢出多波長。 〇 【實施例6】 (源自蘋果未熟果之空胞化毒素中和劑之調製) 將蘋果未熟果(平均重量5 〇32)4〇〇§與1%鹽酸酸性曱醇 I進行均負化後,一面加熱回流一面萃取(3次),將萃取液 減壓濃縮並餾去曱醇後,添加三氣曱烷進行分配(2次),再將 15水層回收,以過濾後蒸餾水混為200ml。更以利用Sep-pakC18 之固相萃取法來進行精製,將之冷凍乾燥而得到空胞化毒素中 【貧施例7】 (錠劑、膠囊劑) 乳糖 硬脂酸鎂 合計 ,實施例5所得物質i〇.〇g 乳糖 75.0g 15.0g lOO.Og 將上述各重量份均勻混合,依據一般方法製作錠劑、膠囊 劑。又,分別添加實施例1、2、3、 例5所得物質,以同樣製作得到錠劑、膠囊劑。
17 1279231 【實施例8】 (散劑、顆粒劑) 據實施例5所得物質20.0g 澱粉 乳糖 合計 30.0g 50.0g 100.Og 將上述各重量份均句混合,依據一般方法製作散劑、顆粒 劑。又,分別添加實施例1、2、3、4、6所得物質來取代實施 5 例5所得物質,以同樣製作得到錠劑、膠囊劑。 【實施例9】 (注射劑) 據實施例5所得物質l.Og 界面活性劑 9.0g 生理食鹽水 90.0g 合計 l〇〇.〇g 將上述各重量份加熱混合、殺菌而作成注射劑。又,分別 添加實施例1、2、3、4、6所得物質來取代實施例5所得物質, 10 以同樣製作得到注射劑。 【實施例10】 (#) 蔗糖 20.0g 水飴(75%固形份)70.0g 水 9.5g 著色料 〇.45g 香料 0.045g 據實施例5所得物質0.005g 合計 l〇〇.〇g 利用上述各重量份之各成分,依據一般方法製作飴。又, 分別添加實施例1、2、3、4、6所得物質來取代實施例5所得 15 物質,以同樣製作得到飴。 【實施例11】 1279231 (果汁) 濃縮柳橙果汁 果糖 檸檬酸 香料 色素 抗壞血酸鈉 l5.〇g 5.〇g 〇.2g O.lg 〇.l5g 机懷聊W又W Q Q . 據實施例5所得物質〇·〇〇2^ 水 79 s 合計 i〇〇.〇g 刊用上述各重量份之各成分,依據_般 又,分別添加實施例1、2、 去製作果汁 所得物質,以同樣製作得到果汁。〜讀f來取代實施例 【實施例12】 (餅乾) 10 低筋麵粉 全蛋 奶油 砂糠 水 發酵粉 據實施例 合計 5 32.〇g16.〇g I6.0g 25.0g l〇.8g 0-l98g 所得物質0.〇〇2g l〇〇.〇g 利用上述各重量份之各^ 又,分別添加實施例1、2、3 所得物質’以同樣製作得到餅 【實施例13】 ’依據一般方法製作餅乾。 、6所得物質來取代實施例5 空胞化毒素對拉^ 。養細胞之細胞毒性試驗 將來自人類胃癌細胞株之AZ-521細胞或來自人類腎臟癌 細胞株之G401細皰調整為2 〇><l〇5cells/mi之懸浮液。將該懸 浮液1〇〇//1分別注入96井皿後,放置一晚調製各個細胞之單 19 1279231 層膜。另外,混合固定濃度之空胞化毒素、及各種濃度之實施 例5或6所得之空胞化毒素中和劑,於37°C、進行30分鐘培 育後,添加在上述96井皿。使空胞化毒素之最終濃度為 120nM,實施例5或6之最終濃度為〇~ 1 〇〇 # g/mi。將皿在5 %C02 5 環境化、37°C中培養8小時後,藉由空胞吸取中性紅(〇.〇5%PBS 溶液)之程度(Ab540)來評價空胞化毒素對細胞之毒性。其 結果顯示於第4圖及第5圖。視實施例5及6中所得之空胞化 毒素中和劑之濃度使空胞化毒素對AZ-521細胞及G401細胞兩 者造成之細胞毒性無毒化。 10 【實施例14】 與培養細胞之結合 將來自人類胃癌細胞株之AZ-521細胞或來自人類腎臟癌 細胞株之G401細胞調整為2.〇xl〇5cells/ml之懸浮液。將該懸 浮液100//1分別注入96井皿後,放置一晚調製各個細胞之單 I5層膜。另外,將各種7辰度之生物“§己空胞化毒素、與固定濃度 之實施例5或6所付之工胞化毋素中和劑,於37°C、進行30 分鐘培育後,添加在細胞之單層膜。使空胞化毒素之最終濃度 為0〜ΙΟΟηΜ,實施例5或6之最終濃度為1〇//g/ml。將細胞之 單層膜在5%C〇2、抓培養中4小時後,以〇·25%戊二搭固定 20細胞。利用業已抗生物素蛋白標記之辣根過氧化崎(Pharmacia) 及TMBZ色素之發色(Ab450nm)來評價接著於細胞表面之生 物標記空胞化毒素之量。其結果顯示於第6圖及第7圖。視實 施例5及6中所得之空胞化毋素中和劑之濃度,阻礙了空胞化 毒素對細胞之結合。 1279231 【實施例15】 老鼠胃傷害實驗 對業已絕食(僅自由攝取飲水)24小時之4週齡之 C57BL/6J老鼠,利用經口探棒,以每10g體重投予5//g之空 5 胞化毒素及50〜250 // g之實施例5所得空胞化毒素中和劑。該 動物係每一隻以個別蘢子飼育,在投藥48小時後,摘出其胃。 將摘出標本以10%嗎啉固定,於其前後進行實體顯微鏡觀察。 固定標本係進行蘇木精曙紅染色,並依據Ghiara等之方法 (Ghiara· P·,et al· Infect· Immun. 63, 4154-4160. ( 1995 )),將胃 10 傷害程度點數化,進行評價。其結果顯示於表1。實施例5可 有意義地抑制胃之傷害。 【表1】 編號 試劑 胃傷害傷痕 1 填酸緩衝液 1.6±0_8 2 實施例5 (250# g) 1.8±0.8 3 空胞化毒素(5//g) 3.0±0.8 4 空胞化毒素(5//g) +實施例5 (50#g) 2_4±1.0 5 空胞化毒素(5//g) + 實施例 5 ( 100//g) 2.2±0·8* 6 空胞化毒素(5//g) + 實施例 5 (250//g) 2_2±0_8* *是顯示相較於3危險率5%以下而為有意義之差。 【圖式簡單說明】 第1圖是顯示來自忽布花之前花青素類之GPC (膠質透過 15 色層分析)分析結果之圖。 第2圖是顯示來自忽布花之前花青素類之消光度分布之 圖。 第3圖是顯示來自忽布花之前花青素類之HPLC分析結果 之圖。 20 第4圖是顯示在人類胃癌細胞AZ-521之培養細胞中之空 21 1279231 胞化毒素之無毒化之圖(實施例13)。 第5圖是顯示在人類腎臟癌細胞G401之培養細胞中之空 胞化毒素之無毒化之圖(實施例13 )。 第6圖是顯示在人類胃癌細胞AZ-521之培養細胞中,阻 5 礙空胞化毒素接近細胞之圖(實施例14)。 第7圖是顯示在人類腎臟癌細胞G401之培養細胞中,阻 礙空胞化毒素接近細胞之圖(實施例14)。 【主要元件符號說明】 無 22
Claims (1)
- 號專利申請案申請專利範圍本 ______,**_’·Lm^ /々ml修正日期:95年11月十、申請專利範圍: 1. 2. 4. 5. 6. 8. 一種幽門螺旋桿菌所產生之空胞化毒素之中和劑,係含有 前花青素類作為有效成分。 如申請專利範圍第1項之空胞化毒素之中和劑,其中該前花 青素類係從忽布花或忽布花苞萃取而得者。 如申請專利範圍第1項之空胞化毒素之中和劑,其中該前花 青素類係從蘋果萃取而得者。 一種消化器官疾病之預防劑、預防復發劑或治療劑,係具 有中和(無毒化)幽門螺旋桿菌產生之空胞化毒素之效果以 預防、預防復發或治療該消化器官疾病者,其係含有前花 青素類作為有效成分。 如申請專利範圍第4項之消化器官疾病之預防劑、預防復發 劑或治療劑,其中該前花青素類係從忽布花或忽布花苞萃 取而得者。 如申請專利範圍第4項之消化器官疾病之預防劑、預防復發 劑或治療劑,其中該前花青素類係從蘋果萃取而得者。 一種可中和幽門螺旋桿菌產生之空胞化毒素的醫藥部外 品,係含有前花青素類作為有效成分者。 如申請專利範圍第7項之醫藥部外品,其中該前花青素類係 從忽布花或忽布花苞萃取而得者。 如申請專利範圍第7項之醫藥部外品,其中該前花青素類係 從顏果萃取而得者。 一種可中和幽門螺旋桿菌產生之空胞化毒素的飲食品,係 含有前花青素類作為有效成分者。 23 9. 1279231 11. 如申請專利範圍第10項之飲食品,其中該前花青素類係從 忽布花或忽布花爸萃取而得者。 12. 如申請專利範圍第10項之飲食品,其中該前花青素類係從 蘋果萃取而得者。 524
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CN103570664B (zh) * | 2013-11-13 | 2015-07-01 | 长沙蓝威生物制品有限公司 | 一种从越橘中提取原花青素的方法 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8518289D0 (en) * | 1985-07-19 | 1985-08-29 | Inverni Della Beffa Spa | Obtaining proanthocyanidine a2 |
JPH09221484A (ja) * | 1996-02-14 | 1997-08-26 | Kikkoman Corp | プロアントシアニジンの製造法 |
JP2000506901A (ja) * | 1996-04-02 | 2000-06-06 | マーズ・インコーポレイテツド | カカオ抽出化合物及び同一物を製造及び使用するための方法 |
JPH1025247A (ja) * | 1996-07-10 | 1998-01-27 | Asahi Breweries Ltd | 胃炎、胃・十二指腸潰瘍の予防及び治療剤 |
JPH10218769A (ja) * | 1997-02-06 | 1998-08-18 | Kikkoman Corp | 抗潰瘍剤 |
US5972985A (en) * | 1997-11-03 | 1999-10-26 | Cytos Pharmaceuticals, Llc | Histidine containing nutriceutical compositions |
JPH11180888A (ja) * | 1997-12-24 | 1999-07-06 | Otsuka Pharmaceut Co Ltd | ヘリコバクター・ピロリ菌用の抗菌剤、感染予防剤および食品 |
JP2000159669A (ja) * | 1998-11-26 | 2000-06-13 | Mikoo:Kk | ウレアーゼ阻害剤及びこれを含有する医薬及び食品組成物並びにウレアーゼ活性測定方法 |
EP1374884A4 (en) * | 2001-03-28 | 2009-08-26 | Asahi Breweries Ltd | NEUTRALIZATOR OF PROTEOTOXINES |
JP2003026587A (ja) * | 2001-07-11 | 2003-01-29 | Nobuo Yamaguchi | ヘリコバクター・ピロリ菌に対する除菌剤 |
US20030161841A1 (en) * | 2002-02-01 | 2003-08-28 | Kazuo Sakuma | Preventive and therapeutic agents for microbe-related syndromes including HIV |
-
2004
- 2004-09-30 TW TW093129616A patent/TWI279231B/zh active
- 2004-10-04 JP JP2005514515A patent/JPWO2005032542A1/ja active Pending
- 2004-10-04 KR KR1020067006399A patent/KR100803375B1/ko not_active IP Right Cessation
- 2004-10-04 WO PCT/JP2004/014979 patent/WO2005032542A1/ja active Application Filing
- 2004-10-04 CN CN2004800288070A patent/CN1863524B/zh not_active Expired - Fee Related
- 2004-10-04 US US10/574,482 patent/US20070009619A1/en not_active Abandoned
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2008
- 2008-03-03 US US12/041,550 patent/US20080275109A1/en not_active Abandoned
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CN1863524B (zh) | 2010-10-06 |
JPWO2005032542A1 (ja) | 2007-11-15 |
US20080275109A1 (en) | 2008-11-06 |
KR20060058729A (ko) | 2006-05-30 |
US20070009619A1 (en) | 2007-01-11 |
KR100803375B1 (ko) | 2008-02-13 |
TW200522973A (en) | 2005-07-16 |
WO2005032542A1 (ja) | 2005-04-14 |
CN1863524A (zh) | 2006-11-15 |
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