TW205542B - - Google Patents
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- TW205542B TW205542B TW080104654A TW80104654A TW205542B TW 205542 B TW205542 B TW 205542B TW 080104654 A TW080104654 A TW 080104654A TW 80104654 A TW80104654 A TW 80104654A TW 205542 B TW205542 B TW 205542B
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
205542 A 6 B6 經濟部中央標準局貝工消費合作社印製 五、發明説明(1 ) I明背景_ 高血三酸甘油酯是一種疾病狀況,其中在血漿中存在 過量的三酸甘油酯。高血三酸甘油酯可造成各種不要的作 用。例如,高血三酸甘油酯可造成某些不正常脂蛋白濃度 之增加,其在動脈粥樣形成及冠狀心臓疾病發展上扮演重 要的角色。此外,已知高血三酸甘油酯為急性胰臓炎的病 因,此疾是可威脅生命之病況。因此希望有一種方法,可 以減低高血三酸甘油酯病人血漿中之三酸甘油酯。 飲食中的三酸甘油酯於腸中水解成單甘油酯及脂肪酸 。這些水解産物被腸粘膜吸收,由此再合成三酸甘油酯。 這些三酸甘油酯再納入脂蛋白中,稱為乳糜微粒,其中含 膽固醇,磷脂及三酸甘油酯,加上蛋白質組合。富含三酸 甘油酯的乳糜微粒分泌至血流中,利用淋巴糸統。循環的 乳糜徹粒曝於酵素一脂蛋白脂酶之下,其可將乳糜撤粒三 酸甘物酯催化成游離的脂肪酸。一旦移去大部份三酸甘油 酯之後,則剩下富含膽固醇之乳糜微粒再由肝自血流中移 除。 此外,肝分泌至血流中的是内源性富含三酸甘油酯的 脂蛋白,稱極低密度脂蛋白(VLDL)。一旦VLDL 循環時,與VLDL相關的三酸甘油酯部份可被由脂蛋白 脂酶及肝三甘油脂酯酶所催化的脂肪分解所移除。於此同 時,循環的VLDL自其他循環的脂蛋白中拾起瞻固醇脂 ,如高密度脂蛋白(HDL)。循環的VLDL繼缠進行 這些修飾變化,造成逐漸變小的粒子,其中缺乏三酸甘油 本紙張尺度边用中國國家標準(CNS)甲4規格(210x297公*) - 3 - ^05542 A 6 B6 經濟部中央標準局貝工消費合作社印製 五、發明説明(2 ) 酯而富含瞻固醇酯。缺令三酸甘油酯的VLDL被肝清除 ,或進一步降解成另一型式的脂蛋白,稱為低密度脂蛋白 (LDL)。雖然,LDL正常下攜帶相當少量的三酸甘 油酯,且於三酸甘油酯血中蓮送中不扮演重要角色,各種 流行病學研究顯示:LDL膽固醇濃度與冠狀心臓疾病之 危險性有相互關像〔Patton et al·,Clin· Chem. 29, 1890(1983)〕。減低不正常高的LDL膽固醇濃度可有效 地治療動脈粥樣硬化,此點通常可為精於此技藝人士所接 受。 病人所存在的高血三酸甘油酯可造成所有循環脂蛋白 的不正常。内源性高血三酸甘油酯可造成延長的乳糜微粒 血症及於攝食脂質後可增加部份代謝的乳糜微粒殘塊。高 血三酸甘油酯也與循環中VLDL增加的滯留時間有關, 且造成VLDL組成中許多變化。這些經修飾的VLDL 很容易被巨噬細胞所拾起,形成脂質泡沫細胞,其最終造 成動脈粥樣硬化。LDL及HDL中各種組成的變化也可 能是高血三酸甘油酯所致,而造成不正常的LDL及 Η P L 〇 雖然高血三酸甘油酯之存在本身不産生粥瘤,因為三 酸甘油酯本身不聚積於動脈硬化斑中,且增高的血漿三酸 甘油酯於流行病研究中似乎不是冠狀心臓疾病獨立的危險 因素,高血三酸甘油酯可造成某些不正常循環脂蛋白之形 成,其本身可能是可産生粥瘤的〔見Vega and Grundy, Adu. Exp. Med. Biol. 243, 311 (1989)〕。因此減低高 本紙張尺度通用中困H家標準(CNS)甲4規格(210x297公龙)-4 - ▼·····♦♦··♦♦·♦···· (請先閱讀背面之注意事項再填P本頁) 205542 A 6 B6 經濟部中央標準局貝工消費合作社印製 五、發明説明(3 ) 血三酸甘油酯病人之三酸甘油酯濃度,可提供減少某些不 正常致粥瘤性脂蛋白濃度之有益作用。 急性胰臓炎是一種自身消化過程,由酶原在胰臓内過 早活化至相當的活性消化酵素所致。增高的循環三酸甘油 酯水平可引起急性胰臓炎之侵襲是已可為人所接受的。進 一步可接受的是急性胰臓炎侵襄之再復發,可針對降低血 漿中三酸甘油酯濃度處理而預防〔見K· Soergel, ACUT-E PANCREATITIS, in Gastrointestinal Disease 91, 3 rd ed· (Sleisenger,Μ· H·,and Fordt ran. J . S·, eds*),W . B · Saunders Company,Philadelphia,Pa·, 1983, pp. 1462-1485; and See Brown, M· S·, and Goldstein, J. L., DRUGS USED IN THE TREATMENT OF HYPERLIPOPROTEINEMIAS» in Goodman and Gillman's» The Pharmacological Basis of Therapeutics 34, 7th edition, (Macmillan Publishing Co . , New York,1985 ,pp· 827-845〕〇 本發明是有關使用某些雙(3, 5 —二烷基一 4 一羥 苯硫基)甲烷類,如雙(3, 5 —二第三· 丁基一 4 一羥 苯硫基)甲烷,治療罹患高血三酸甘油酯病人。雙(3, 5—二第三.丁基一4一羥苯硫基)甲烷,掲示於美國專 利第4, 900, 757號中,可於接受治療的病人身上 提供降血膽固醇及抗動脈粥樣硬化之效應。 發明要點 本紙張尺度通用中《國家標準(CNS)甲4規格(210x297公嫠)_ 5 - η 先 閲 售ϊ 背 之 注 意 事 項 再 填一 本 頁 裝 訂 線 205542 A6 B6 五、發明説明(4 ) 本發明提出於有所需的病人中降低血漿三酸甘油酯之 方法,此方法包括對病人投予可有效降血三酸甘油酯劑量 的下式(I )化合物 Κι
R3 S-CH2-S
OH ⑴ 其中Rh R2, R3及R4各自獨立地為一 Ce烷基。 本發明進一步提出治療高血三酸甘油酯病人的方法, 此方法包括對該病人投予有效降血三酸甘油酯劑量的式 I )化合物。 (請先閲讀背面之注意事項再填t本頁) 裝* 線· 經濟部中央標準局貝工消費合作社印製 發J月的詳細說明 如此中所用的,> C』一 Cs烷基〃一詞表示且包括由 1至6個硪原子組成的直,環狀或分支鍵構型的飽和烷基 。包括在此各詞範圍内的有甲基,乙基,正丙基,異丙基 ,正丁基,異丁基,第二.丁基,第三.丁基等。式(I )化合物,其中Ri, R2, R3及R4各自為第三.丁基, 或雙(3, 5 —二第三· 丁基一 4 一羥苯硫基)甲烷,於 依據本發明的使用方法中為較佳者。 此中所用的病人,俗指溫血動物或哺乳動物,包括齧 齒類及人類,偽需治療高血三酸甘油酯者。需治療高血三 本紙張尺度逍用中國國家標準(CNS)甲4規格(210x297公*) - 6 - 205542 經濟部中央標準局員工消費合作社印製 五、發明説明(5 ) 酸甘油酯之病人,如於罹患IV型高脂蛋白血症者(有提 高的VLDL水平),此像依據弗瑞迪克森分類〔Fredrickson and Levy, FAMILIAL HYPERLIPOPROTEINEMIA, in The Metabolic Basis of Inherited Disease, 3rd ed. (Stanbury. J. B. ; Wyngaarden. J. B. ; and Fred rickson. D. S·; eds.) McGraw-Hill Book Co., New Y-ork, 1972, pp. 545-614〕。 高血三酸甘油酯是一種疾病狀態,其特擻為血中三酸 甘油酯濃度,較一般精於此技藝人士所認定之正常值有顯 著提高。需高血三酸甘油酯治療的病人之鑑定,是在精於 此技藝人士之能力及知識範圍之内。例如,由臨床實驗室 試驗決定出,其血中三酸甘油酯濃度較一般精於此藝人士 所認定之正常值有實質地且慢性提高者,為需進行高血三 酸甘油酯治療之病人。經由進一步實例,具有發展成高血 三酸甘油酯危險性的個體,也可視為需進行高血三酸甘油 酯治療之病人。精於此技藝之醫師,經由臨床試驗,身體 檢査及家庭病史可容易地鑑定出罹患高血三酸甘油酯之病 人,及具有發展成高血三酸甘油酯危險性者,且因此可容 易地決定該値體是否為需進行高血三酸甘油酯治療之病人 Ο 式(1)化合物的有效降血三酸甘油酯劑量,為可於 有所需病人中有效降低血漿三酸甘油酯濃度之劑量。如此 可了解,對高血三酸甘油酯病人成功的治療包括減低病人 的血漿三酸甘油酯濃度。也可了解高血三酸甘油酯成功的 η 先 閲 背 面 之 注 意 事 項 再 填 本 頁 本紙張尺度適用中SB家標準(CNS)甲4規格(210x297公嫠)_ 7 - A 6 B6 205542 五、發明説明(6 )
i 先 閱 背 之 注 意 事 項 再 I 治療,包括於具有發展成高血三酸甘油酯危險性之病人, 避免血漿三酸甘油酷水平有臨床上顯著提高之預防治療。 有效的降血三酸甘油酯劑量可由習知的技術及由類似 狀況下所觀察得到之結果而容易地決定。於決定有效劑量 時,要考慮的許多因素包括下列,但亦不限於此:病人種 類,其體型大小,年齡及一般健康狀態;所涉及之特殊疾 病;疾情嚴重情形;個體反應;所投予之持殊化合物;投 藥模式;所投予製劑之生物利用率特性;所選用之劑量設 計;及共同投予之藥物。 式(1)化合物之有效降血三酸甘油酯劑量,通常由 毎天毎公斤體重約1毫克(毫克/公斤/天)變化至約每 天每公斤體重5克。以每天劑量由約1毫克/公斤至約 5 0 0毫克/公斤為較佳。 經濟部中央標準局貝工消費合作社印製 於有效治療病人時,式(1)化合物可以使化合物呈 有效劑量而可生物利用地任何型式或模式投予,包括口服 及腸外路徑。例如,化合物可口服,皮下,肌内,靜脈内 ,穿皮,#内,經宜腸等投藥。以口服為較佳。精於製備 調和物人士可依欲治療之疾病狀態,疾病階段,及其他相 關條件而容易地選擇適當的型式及模式。 式(1)化合物可呈藥學組成物或藥物型式投予,其 由式(1)化合物與藥學上可接受之載體或賦形劑混合而 製成,其比率及本質可由所選用之投藥路徑及檫準藥學操 作而決定。 藥學組成物或藥物,以藥學技藝中熟知之方式製備。 本紙張尺度遑用中國國家揉準(CHS)甲4規格(210 x 297公*) - 8 - 205542 A 6 B6 經濟部中央標準局员工消費合作社印製 五、發明説明(7 ) 載體或賦形劑可為固體,半固體,或液體物質,其可充作 活性成份之溶媒或介質。適當的載體或賦形劑是技藝中已 知的。藥學組成物可使適用於口服或腸外使用,且可呈錠 劑,膠囊劑,栓劑,溶液劑,懸浮劑等型式投予至病人。 藥學組成物可口服,如加上惰性稀釋劑或加上可食性 載體。也可包膠於明膠膠囊中或壓製成錠。於口服治療投 藥目的,式(1)化合物可與賦形劑一起納入,且以錠劑 ,片劑,膠囊劑,酏劑,懸浮劑,糖漿劑,扁Η劑,咀嚼 膠等型式使用。這些製劑應該含有至少4%的式(1)化 合物一即活性成份,但可依特殊型式變化,且可在4%至 70%的按單位重量下合宜地變化。組成物中所存在之活 性成份劑量如此,因此可獲得適於投藥之單位劑量型式。 錠劑,丸劑,膠囊劑,片劑等因此可含下列一種以上 之佐劑:粘合劑,如徹晶體纖維素,西黃耆膠或明膠;賦 形劑,如澱粉或乳糖,崩散劑如藻酸,Primosel,玉米锻 粉等;潤滑劑,如硬脂酸鎂或Sterotex;助流劑,如膠體 二氧化矽;及甜味劑,如蔗糖或糖精,或芳香劑,如薄荷 油,水揚酸甲酯或橘子香料。當劑量單位型式為膠囊劑時 ,除了上述型式之物質之外,其可含液體載體,如聚乙二 醇或脂油。其他劑量單位型式可含其他各種變化劑量單位 物理型式之各種物質,如包衣。因此,錠劑或丸劑可覆以 糖,蟲膠,或其他腸衣劑。糖漿劑除了活性成份之外,可 合有蔗糖為甜味劑及某些保藏劑,染料及著色劑及香料。 用於製備各種組成物之物質應該是藥學上純的,且於所使 本紙張尺度通用中國B家標準(CNS)甲4規格(210x297公釐)-9 - 205542 A 6 B6 經濟部中央標準局貝工消費合作社印製 五、發明説明(8 ) 用之劑量下是無毒的。 於腸外投藥目的,式(1)化合物可納入溶液劑或懸 液劑中。這些製劑應含有至少 0.1%的本發明化合物 ,但可變化在其重量的Ο.1至約50%之間,存在於此 組成物中之活性成份劑量是如此,因此可獲得適當的剤量 〇 溶液劑或懸浮劑也可含以下一種以上之佐劑:無菌的 稀釋劑,如注射用水,食鹽水溶液,固定油,聚乙二醇, 甘油,丙二醇或其他合成的溶劑;抗菌劑,如苄醇或羥苯 甲酸甲酯;抗氣化劑如抗壞血酸或亞硫酸氫鈉;嵌合劑, 如乙底酸;緩衝溶液如醋酸鹽,檸樣酸鹽,或磷酸鹽,及 調整等滲性之作用物,如氣化鈉或右旋糖。腸外用製劑可 密封於安瓿,可無棄式注射器或多劑量小瓶中,材質為玻 璃或塑質。 式(1)化合物可由一般精於此技藝人士以已知及了 解之方法製備。例如,式(1)化合物可由乙腈及DOW EX50樹脂存在下,在迴流條件中處理適當的2, 6— 二烷基一 4 —魏基酚與1, 3, 5 —三噁烷而成。2,6 一二烷基一 4 一魏基酚可如所述般製備,如krauss於美 國專利第4, 734, 527號中所述,其中掲示2, 6 一二第三.丁基一4一魏基酚之製備。 由本發明所提供之最終使用應用中,較佳的式(1) 化合物是雙(3, 5 —二第三.丁基一 4 一羥基苯硫)甲 烷。以下實例說明雙(3, 5 —二第三.丁基一 4 一羥基 η 先 閲 讀 背 φ 之 注 意 事 項 再 塡 r 本 頁 衣紙張尺度逍用中國國家楳準(CNS)甲4規格(210x297公釐)-10 - ^66205542 五、發明説明(9 ) 苯硫)甲烷,依據本發明之製備及用途。這些實例僅供說 明,不欲以任何方式限制本發明。 窗例 經濟部中央標準局員工消費合作社印製 靱備等(3. 5 —二第三.丁某一 4 —镩苯硫基)甲烷 於三頸燒瓶中混合物乙睛〔1800毫升〕,1, 3 ,5 -三噁烷(71. 0毫升,0. 79莫耳),2, 6 _二第三.丁基—4—頸基酚(678. 4克,2. 85 莫耳)及50克的DOWEX50樹脂。在氮大氣下令 混合物達迴流,並保持36—48小時以生成標題化合物 Ο 過濾混合物以除去D0WEX50樹脂,並於真空下 濃縮濾液,以生成褐色油狀物。油溶於1升乙醇中(70 1C下)並加入1 25毫升水。令混合物冷卻至環境溫度一 夜,而仍攪拌。以過濾收集生成之結晶産物,再以7 5毫 升冷乙醇/水/90/10)洗濾塊。自乙醇/水中再結 晶産物,並過濾收集。以50毫升冷乙醇洗濾塊,於50 *0及15毫米Hg下真空乾燥産物,生成406· 9克純 的標題化合物,呈白色固體。熔點94 — 951。元素分 析: 估計值——C = 71. 3%, H = 9. 07%; 實測值——C = 71. 3%, H = 9. 07% ? 先 閲 讀 背 面 之 注 意 事 項 再 本 1 裝 訂 線 各紙張尺度逍用中aa家標準(CNS)甲4規格(210x297公*)- 11 - 205542 A 6 B6 五、發明説明(10) 曹例2 «£ (3. 5—二第三.丁某一4一瘅荣硫基)甲烷之睦 rfn三酿甘油酯作用 老鼠分成4或5隻一組的2値治療組,並如下處理 2 1天: 第一組(對照組,4隻)一動物餵以標準齧齒類口糧 第二組(處理組,5隻)一動物餵以含0. 25%雙 3, 5—二第三.丁基一4一羥苯硫基)甲烷 之標準齧齒類口糧 21天之後,動物殺死並採血。以標準酵素方法,利 用 DACOS 分析儀(Coulter Electronics,Inc., Hialeah, Florida, USA) 決 定血中三酸甘油酯。 老鼠以雙(3, 5 —二第三.丁基一 4 一羥苯硫基) 甲烷處理之結果示於表1。 請 先 閲 讀 背 面 之 注 意 事 項 再 本 頁 裝 訂 線 經濟部中央標準局貝工消費合作社印製 本紙張尺度逍用中國8家標準(CNS)甲4規格(210x297公¢) _卫之_ 2〇S542 A 6 B6 五、發明説明(11) 表 劈(3. 5-二第二--丁基—4 —翔采硫基)甲院 於老鼠體内之作用 處理組 血漿三酸甘油酯 (毫克/1 00毫升士 S.D·) 1 ·對照組 273± 80 2.組成物A 87± 20* η 先 閱 背 之 注 意 事 項 再 塡Τ 本 Η 裝 訂 經濟部中央標準局貝工消費合作社印製 化合物Α二雙(3,5 —二第三.丁基一 4 一羥苯硫基) 甲烷 *p<〇. 00 1 這些結果顯示,投予雙(3, 5_二第三.丁基一 4 一羥苯硫基)甲烷至老鼠,可造成血漿三酸甘油酯濃度統 計學上顯著的減低。 基於以上,式(1)化合物可用於製成藥物以治療高 血三酸甘油酯病人,及降低血漿之三酸甘油酯。 線 本紙張尺度逍用中國國家標準(CNS)甲4規格(210X297公釐)-13 -
Claims (1)
- A7 B7 C7 D7第80104654號專利申請案 中文申請專利範圍修正本 R3 5-CH2-5OH 六、申請專利範圊 附件1 ( A) 民國81年4月修正 ! 1.一種可ώ低血漿三酸甘油酯之藥學組成物,其中 包括有效降血三^甘油酯劑量之下式化合物 Ri其中Ri, R2, R3及R4各自獨立地是Ci_Ce烷基,並 混合至少一種藥學上可接受之載體。 2. —種治療罹患高血三酸甘油酯之藥學組成物,其 包括有效降血三甘油酯劑量之下式化合物 (請先閲讀背面之注意事頊再填寫本頁) 經濟部屮央櫺:?局Μ工消伢合作杜印製 ‘RiR3 5-CH2-SOH 其中R i,R 2,R a及R 4各自獨立地為C C 6烷基·並 混合至少一種藥學上可接受之載體。 木紙张尺度適川十网明家梂平(CNS)叩4規格(210x297公竑) A 7 B7 C7 D7 2〇5542 六'申請專利範圊 3 .如申請專利範圍第1或2項之組成物,其中的化 合物是雙(3 , 5 _二特丁基 一 4 一羥苯硫基)甲烷。 (請先閱讀背面之注意事項再填寫本頁) .故· .線. 經濟部屮央標?^AW工消费合作作印製 -2 - 木紙张尺度逋川肀H3 W家楳準(CNS),P 4规格(210 X 297公犮)
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EP0462556A2 (en) | 1991-12-27 |
DE69113871D1 (de) | 1995-11-23 |
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ATE129151T1 (de) | 1995-11-15 |
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EP0462556B1 (en) | 1995-10-18 |
GR3018351T3 (en) | 1996-03-31 |
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US5122542A (en) | 1992-06-16 |
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KR0168649B1 (ko) | 1999-01-15 |
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