TWI314868B - Pharmaceutical preparation containining 5-methyl-1-phenyl-2-(1h)-pyridone as an active ingredient - Google Patents

Pharmaceutical preparation containining 5-methyl-1-phenyl-2-(1h)-pyridone as an active ingredient Download PDF

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TWI314868B
TWI314868B TW091101440A TW91101440A TWI314868B TW I314868 B TWI314868 B TW I314868B TW 091101440 A TW091101440 A TW 091101440A TW 91101440 A TW91101440 A TW 91101440A TW I314868 B TWI314868 B TW I314868B
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tablet
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hydroxypropylcellulose
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Kiyonaka Gakuji
Furuya Yoshihiro
Suzuki Yusuke
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Shionogi & Co
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

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Description

1314868 五、發明說明（1 ) 技術領域 本發明係關於一種以5 -甲基-1-苯基- 2- (1Η)·吡啶酮爲 有效成分之錠劑。 背景技術 5 -甲基-1-本基- 2- (lH)'Rth陡嗣（一般名：匹爾薬尼嗣 Pir fen i done)爲對肺纖維症爲對象疾病之藥劑。關於匹爾 棻尼酮，至今報告有各種效果。例如，1)對肺或動脈硬化 巢等之纖維化具有治療效果者，如特開平2-215719; 2)其 類緣體亦具有同樣之作用者，如特表平8-510251; 3)有用 於呼吸器或皮膚之炎症症狀之治療者，USP3,974,281、 USP4,042,699、USP4,0 5 2,509 ; 4)抑制 TNF - α 之合成及釋 放者，如特表平1 1 - 51 2699。 匹爾棻尼酮之劑型，例如上述之1)及2)爲膠囊劑、錠 劑、散劑、顆粒劑、糖漿劑、注射劑、霜劑、軟膏劑、吸 入劑、點眼劑、塞劑、及九劑，但較佳之劑型爲膠囊劑、 注射劑、霜劑、及軟胥劑，實施例僅記載爲膠囊劑及軟膏 劑。即對於匹爾棻尼酮的錠劑，並未有具體之記載。 /關於匹爾棻尼酮的投予量，上述1)中記載爲1日3回內 服600mg至2400rag。另2)之試驗例1中記載含有8 00mg、 1 200mg、及1 600mg之匹爾棻尼酮的膠囊劑。爲使如此投 予匹爾棻尼酮獲得充分之效果，必須明顯較通常藥劑服用 較多量。 此處，膠囊有000、00、0、1、2、3、4及5號等8種 1314868 五、發明說明（2) ’數字越大者尺寸越小。雖然塡充之藥劑的體積密度、壓 縮性等會有影響，但一般而言，5號膠囊可塡充 6〇1^~1〇〇111£、4號膠囊可.塡充10〇11^〜17〇11^、3號膠囊可塡 充140rog〜220mg、2號膠囊可塡充180mg~3 00mg、1號膠囊 可塡充240mg〜390mg、0號膠囊可塡充340mg~540mg之藥 劑。投予人之膠囊多使用2〜4號膠囊，但最近爲做成易於 飮用而傾向小型化，則多使用3〜5號膠囊。又膠囊中塡充 之藥劑通常並不僅有活性成分，爲提升活性成分之安定性 及有效性，加入賦形劑、結合劑、崩壞劑等，予以製劑化 而使用。 例如將匹爾棻尼酮1回投予量做成上述600ing時，爲以 膠囊劑投予，塡充於膠囊內之製劑化工程的匹爾棻尼酮顆 粒或混合粉末爲約800mg〜850mg。爲了將此等塡充於1個 膠囊，必須使用00 0號膠囊。而爲了將此等塡充於2個膠 囊，必須使用0號膠囊，患者服用時則伴隨顯著的痛苦。 在更多情形下，要將投予量做成實用之膠囊劑，有事實上 的困難。 發明之掲示 —般經口投予時，錠劑較膠囊劑易於服用。因此’本發 明人等檢討在經口投予大量匹爾棻尼酮之際’有效改善匹 爾棻尼酮的錠劑之製劑化。然而，在此過程中’發現有D 匹爾棻尼酮具特有臭味及苦味、2)匹爾棻尼酮單劑時壓 縮性低、及3 )光安定性之問題。 1314868 五、發明說明（3) 本發明人等有鑒於上述問題，反覆蓄意檢討之結果，發 現一種遮掩臭味及苦味、提升光安定性、確保快速之溶出 速度及安定性，不僅主藥含量多且壓縮時具充分之硬度、 順從性的改善之匹爾棻尼酮錠劑，完成本發明。 即本發明爲 1) 含有5 -甲基-1-苯基- 2- (1Η) -吡啶酮爲主藥之錠劑。 2) 錠劑重量爲100~1 000iLg之1 )錠劑。 3) 對錠劑重量而言，含有10~85重量％之主藥的1)或2) 之錠劑。 4) 主藥含量爲200〜400rog之1)至3)任一項之錠劑。 5) 含有遮光劑之1 )至4 )任一項之錠劑。 6) 對主藥而言，含有〇.〇5〜3重量％之遮光劑的5)之錠劑 〇 7) 對主藥而言，含有1〇~50重量％之賦形劑、5~40重量％ 之崩壞劑、1 ~ 1 0重量％之結合劑、0 · 5 ~ 5重量％之潤滑 劑、2~6重量％之包衣基劑、及0.05~3重量％之遮光 劑各劑的1 )至4 )任一項之錠劑。 8) 對主藥而言，含有〇.〇1~1重量％之可塑劑的7)之錠劑 〇 9) 對主藥而言，含有ι〇~50重量％之賦形劑、5~40重量％ 之崩壞劑、1〜10重量％之結合劑、及0.5~5重量％之 潤澤劑各劑的素劑，及對主藥而言，含有2~6重量％ 之包衣基劑及〇 · 〇5〜3重量％之遮光劑各劑的包衣層所 1314868 五、發明說明（4) 構成之1)至4)任一項之錠劑。 10) 在包衣層中，含有對主藥爲0.01~1重量％之可塑劑的 9)之錠劑。 11) 對主藥而言，含有選自乳糖、玉米澱粉、及結晶纖維 素之10〜5 0重量％之賦形劑；選自羧甲基纖維素 (Carmellose)鈣、低取代之羥丙基纖維素、及交聯聚 乙烯吡咯酮之5~40重量％之崩壞劑；選自羥丙基纖維 素及聚Z烯吡咯酮之1〜10重量％之結合劑；及選自硬 脂酸鎂及滑石之0.5〜5重量％之潤滑劑各劑之素劑， 以及對主藥而言，含有選自羥丙基甲基纖維素及羥丙 基纖維素之2〜6重量％之包衣基劑；選自檸檬酸三乙 酯及三乙酸甘油酯之重量％之可塑劑；及選自 氧化鈦及三氧化二鐵之0.05〜3重量％之遮光劑各劑之 包衣層所構成的1)至4)任一項之錠劑。 12) 對主藥而言，含有10〜50重量％之乳糖、5〜40重量％之 羧甲基纖維素鈣、1~1〇重量％之羥丙基纖維素、及 0.5〜5重量％之硬脂酸鎂各劑之素劑，以及對主藥而 言，含有2〜6重量％之羥丙基甲基纖維素、重 量％之檸檬酸三乙酯、及〇.〇5~3重量％之氧化鈦各劑 之包衣層所構成的11)之錠劑。 13) 對主藥而言，含有選自乳糖、玉米澱粉、及結晶纖維 素之20〜3 0重量％之賦形劑；選自羧甲基纖維素鈣、 低取代之羥丙基纖維素、及交聯聚乙烯吡咯酮之 1314868 五、發明說明（5) 7.5~15重量％之崩壞劑；選自羥丙基纖維素及聚乙烯 吡咯酮之2~5重量％之結合劑；及選自硬脂酸鎂及滑 石之0.5〜3重量之潤滑劑各劑之素劑’以及對主藥 而言，含有選自羥丙基甲基纖維素及羥丙基纖維素之 2~4重量％之包衣基劑；選自檸檬酸三乙酯及三乙酸 甘油酯之0.01~1重量％之可塑劑；及選自氧化鈦及三 氧化二鐵之0.8~3重量％之遮光劑各劑之包衣層所構 成的1)至4)任一項之錠劑。 14)對主藥而言，含有20~ 30重量％之乳糖、7.5〜15重量％ 之羧甲基纖維素鈣、2~5重量％之羥丙基纖維素、及 0.5〜3重量％之硬脂酸鎂各劑之素劑，以及對主藥而 言，含有2~4重量％之羥丙基甲基纖維素、0.01〜1重 量％之檸檬酸三乙酯、及0.8~3重量％之氧化鈦各劑之 包衣層所構成的13)之錠劑。 本說明書中之「賦形劑」爲用於通常製劑製造之賦形劑 。例如輕質無水矽酸、合成矽酸鋁、甲基鋁酸鎂等之矽酸 類；磷酸鈣、碳酸鈣、硫酸鈣等之無機鹽類、乳糖、白糖 、葡萄糖、甘露糖醇、山梨糖醇等之醣類；玉米澱粉、α 澱粉、羧甲基澱粉等之澱粉類；結晶纖維素、低取代度羥 丙基纖維素等之纖維素類；阿拉伯膠、葡聚糖、支鏈澱粉 等。特佳爲乳糖 '玉米澱粉、結晶纖維素等。 本說明書中之「崩壞劑」爲在服用錠劑時，在消化管內 浸潤、崩壞製劑至微粒化，以分散爲目的所使用之添加劑 1314868 五、發明說明（6) 。例如玉米澱粉、羧甲基纖維素、羧甲基纖維素鈣、低取 代度經丙基纖維素、羧甲基纖維素鈉、氯化羧甲基纖維素 鈉、羧甲基澱粉鈉、交聯聚乙烯吡咯酮等。特佳爲羧甲基 纖維素鈣、低取代度羥丙基纖維素、交聯聚乙烯吡咯酮等 〇 本說明書中之「結合劑」爲通常之製劑製造所使用之結 合劑。例如’羥丙基纖維素、羥丙基甲基纖維素、甲基纖 維素、聚乙烯吡咯酮等。特佳爲羥丙基纖維素、聚乙烯吡 咯酮等。 本說明書中之「潤滑劑」爲如滑石、硬脂酸鈣、硬脂酸 鈉、硬脂酸鎂等。特佳爲硬脂酸鎂、滑石等。 本說明書中之「包衣基劑」爲如白糖、滑石、沉澱碳酸 鈣、明膠、阿拉伯膠、支鏈澱粉、羥丙基纖維素、羥丙基 甲基纖維素、聚乙烯吡咯縮醛二乙基胺乙酸、胺烷基甲基 丙烯酸酯共聚物、乙酸對苯二甲酸纖維素、甲基丙烯酸共 聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、羥 丙基甲基纖維素對苯二甲酸、羥甲基丙基甲基纖維素乙酸 琥珀酸、羧甲基乙基纖維素等。特佳爲羥丙基甲基纖維素 、羥丙基纖維素等。 本說明書中之「遮光劑」爲通常製劑製造所用之遮光劑 。例如氧化鈦、三氧化二鐵等。特佳爲氧化鈦。 本說明書中之「可塑性」爲通常製劑製造所使用之可塑 劑。例如檸檬酸三乙酯、三乙酸甘油酯、甘油脂肪酸酯、 1314868 五、發明說明（7) 對苯二甲酸酯類等。特佳爲檸檬酸三乙酯、三乙酸甘油酯 等。 爲實施發明之最佳型態 本發明之錠劑可依如下之A)~D)步驟製造。 A) 調製含有匹爾棻尼酮、賦形劑、及崩壞劑之混合粉末， 使用通常使用的流動層造粒機等，噴灑結合劑並造粒， 獲得顆粒。 B) 在所得之顆粒中加入崩壞劑、潤滑劑等予以混合後，以 8〜18kN、較佳爲1卜15kN打錠，製得匹爾棻尼酮素錠。 C) 調製含有包衣基劑、可塑劑、遮光劑等之包衣液。但亦 可不含可塑劑。 D) 將該包衣液包覆於B)所得之匹爾棻尼酮素錠，獲得目的 之匹爾棻尼酮錠劑。 上述步驟中，亦可適宜添加通常固形製劑使用之添加劑。 本發明爲關於含有以5-甲基-1-苯基-2-(1Η)-吡啶酮爲 有效成分之錠劑，特別錠劑重量較佳爲100~1000mg者， 更佳爲150~700mg，最佳爲240~480mg。對錬劑之重量而 言，較佳含有10〜85重量％之主藥，更佳爲25~85重量％， 最佳爲50~85重量％。主藥之含量較佳爲200mg~400mg者。 如此設計之錠劑比膠囊壓縮，容易服用，且由於主藥含 量多，可發揮有效之藥效。 即本發明之錠劑中亦包含比含有以5 -甲基-1-苯基- 2-(1H) -吡啶酮爲有效成分之膠囊劑更壓縮之錠劑。 1314868 五、發明說明（8) 又本發明人在製造匹爾棻尼酮之錠劑時，始發現其光安 定性之問題，經由添加遮光劑而發現光安定性改善之匹爾 棻尼酮錠劑。且對於主藥而言，較佳含有0.05〜3重量％之 遮光劑的錠劑，且發現包衣層中含有遮光劑之錠劑爲佳。 即本發明之錠劑亦包含含有以5 -甲基-1-苯基- 2-(1Η)-吡啶酮爲主藥之光安定性改善之錠劑。 素錠中除主藥以外的各成分之較佳分配量以對主藥之匹 爾棻尼酮的重量％顯示。但是，由於主藥之匹爾棻尼酮爲 多量，考量易於服用下，應儘少添加其他成分爲佳。然而 ，其他成分過少時，錠劑的硬度可能會降低。故賦形劑較 佳爲 a)10~50重量％，更佳爲b)15~40重量％，最佳爲 c)20〜30重量％。崩壞劑較佳爲d)5~40重量％，更佳爲 e)5〜25重量％，最佳爲〇7.5~15重量％。結合劑爲g)l〜10 重量％，更佳爲h)l~7.5重量％，最佳爲i)2~5重量％。潤 滑劑較佳爲j )0.5~5重量％，更佳爲k)0.5~4重量％，最佳 爲1 )0.5〜3重量％。 包衣液中各成分之較佳分配量以對主藥之匹爾棻尼酮的重 量％顯示。爲遮掩匹爾棻尼酮特有之臭味及苦味，包含有包衣 基劑，而爲提升光安定性，包含有遮光劑，而同素劑之情況 ’應儘少添加其他成分爲佳。故包衣基劑m)較佳爲2〜6重量 %，η)更佳爲2〜5重量％，〇)最佳爲2~4重量％。ρ)遮光劑較佳 爲0.05〜3重量％，q)更佳爲0.05~2重量％，r)最佳爲 0.8〜1.5重量％。可塑劑s)可不含有，含有時t)較佳爲 0.05〜1重量％。 -10- 1314868 五、發明說明（9)本發明之錠劑的各成分對匹爾棻尼酮之適當分配量如以下 所示。即（賦形劑，崩壞劑，結合劑，潤滑劑，包衣基劑，遮 光劑，可塑劑） • = (a, d, g, j, m, p, s), (a, d, g, j, m, p, t), (a, d, g, j, m, q, s), (a, d, g, j, m, q, t), (a, d, g, j, m, r, s), (a, d, g, j, m, r, t), (a, d, g, j, n, p, s), (a, d, g, j, n, p, t), (a, d, g, j, n, q, s), (a, d, g, j, n, q, t), (a, d, g, j, n, r, s), (a, 4, g, j, n, r, t), (a, d, g, j, o, p, s), (a, d, g, j, o, p, t), (a, d, g, j, o, q, s), (a, d, g, j, o, q, t), (a, d, g, j, o, r, s), (a, d, g, j, o, r, t), (a, d, g, k, m, p, s), (a, d, g, k, m, p, t), (a, d, g, k, m, q, s), (a, d, g, k, m, q, t), (a, d, g, k, m, r, s), (a, d, g, k, m, r, t), (a, d, g, k, n, p, s), (a, d, g, k, n, p, t), (a, d, g, k, n, q, s), (a, d, g, k, n, q, t), (a, d, g, k, n, r, s), (a, d, g, k, n, r, t), (a, d, g, k, o, p, s), (a, d, g, k, o, p, t), (a, d, g, k, o, q, s), (a, d, g, k, o, q, t), (a, d, g, k, o, r, s), (a, d, g, k, o, r, t), (a, d, g, 1, m, p, s), (a, d, g, 1, m, p, t), (a, d, g, 1, m, q, s), (a, d, g, 1, m, q, t), (a, d, g, 1, m, r, s), (a,.d, g, 1, m, r, t), (a, d, g, 1, n, p, s), (a, d, g, 1, n, p, t), (a, d, g, 1, n, q, s), (a, d, g, 1, n, q, t), (a, d, g, 1, n, r, s), (a, d, g, 1, n, r, t), (a, d, g, 1, o, p, s), (a, d, g, 1, o, p, t), (a, d, g, 1, o, q, s), (a, d, g, 1, o, q, t), (a, d, g, 1, o, r, s), (a, d, g, 1, o, r, t), (a, d, h, j, m, p, s), (a, d, h, j, m, p, t), (a, d, h, j, m, q, s), (a, d, h, j, m, q, t), (a, d, h, j, m, t, s), (a, d, h, j, m, r, t), (a, d, h, j, n, p, s), (a, d, h, j, n, p, t), (a, d, h, j, n, q, s), (a, d, h, j, n, q, t), (a, d, h, j, n, r, s), (a, d, h, j, n, r, t), (a, d, h, j, o, p, s), (a, d, h, j, o, p, t), (a, d, h, j, o, q, s), (a, d, h, j, o, q, t), (a, d, h, j, o, r, s), (a, d, h, j, o, r, t), (a, d, h, k, m, p, s), (a, d, h, k, m, p, t), (a, d, h, k, m, q, s), (a, d, h, k, m, q, t), (a, d, h, k, m, r, s), "(a, d, h, k, m, r, t), (a, d, h, k, n, p, s), (a, d, h, k, n, p, t), (a, d, h, k, n, q, s), (a, d, h, k, n, q, t), (a, d, h, k, n, r, s), (a, d, h, k, n, r, t), (a, d, h, k, o, p, s), (a, d, h, k, o, p, t), (a, d, h, k, o, q, s), (a, d, h, k, o, q, t), (a, d, h, k, o, r, s), (a, d, h, k, o, r, t), (a, d, h, 1, m, p, s), (a, d, h, 1, m, p, t), (a, d, h, 1, m, q, s), (a, d, h, 1, m, q, t), (a, d, h, 1, m, r, s), (a, d, h, 1, m, r, t), (a, d, h, 1, n, p, s), (a, d, h, 1, n, p, t), (a, d, h, 1, n, q, s), (a, d, h, 1, n, q, t), (a, d, h, 1, n, r, s), (a, d, h, 1, n, r, t), (a, d, h, 1, o, p, s), (a, d, h, 1, o, p, t), (a, d, h, 1, o, q, s), (a, d, h, 1, o, q, t), (a, d, h, 1, o,-1 1 - 1314868 五、發明說明（1〇) ’ r, s), (a, d, h, 1, o, r, t), (a, d, i, j; m, p, s)3 (a, d, i, j, m5 p, t), (a, d, i, j, m, q, s), (a, d, i, j, m, q, t), (a5 d, i, j, m, r, s), (a, d, i, j, m, r, t), (a, d, i, j, n, p, s), (a} d, i, j, n, p, t), (a, d3 i, }, n, q, s), (a, d, i, j, n, q, t)s (a, d, i, j, n, r, s), (a, d, i, j, n, r, t), (a, d, i, j, o, p, s), (a, d, i, j, o, p, t), (a, d, i, j, o, q, s), (a, d, i, j, o, q, t), (a, d, i, j, o, r, s), (a, d, i, j, o, r, t), (a, d, i, k, m, p, s), (a, d, i, k, m, p, t), (a, d, i, k, m, q, s), (a, d, i, k, m, q, t), (a, d, i, k, m, r, s), (a, d, i, k, m, r, t), (a, d, i, k, n, p, s), (a, d, i, k, n, p, t), (a, d, i, k, n, q, s), (a, d, i, k, n, q, t)s (a, d, i, k, n, r, s), (a, d, i, k, η, t, t), (a, d, i, k, o, p, s), (a, d, i, k, o, p, t), (a, d, i, k, o, q, s), (a, d, i, k, o, q, t), (a, d, i, k, o, r, s), (a, d, i, k, o, r, t), (a, d, i, 1, m, p, s), (a, d, i, 1, m, p, 1), (a, d, i, 1, m, q, s), (a, d, i, 1, m, q, t), (a, d, i, 1, m, r, s), (a, d, i, l, m, r, t), (a, d, i, 1, n, p, s), (a, d, i, 1, n, p, t), (a, d, i, 1, n, q, s), (a, d, i, 1, n, q, t), (a, d, i, 1, n, t, s), (a, d, i, 1, n, r, t), (a, d, i, 1, o, p, s), (a, d, i, 1, o, p, t), (a, d, i, 1, o, q, s), (a, d，i, 1，〇, q, （a，d, i，1，〇, t，s), (a，d，i, 1，〇, r，t), (a，e，g, j, m，p，s)，（a，e, g, j，m，p, t)， (a, e, g, j, m, q, s), (a, e, g, j, m, q, t), (a, e, g, j, m, r, s), (a, e, g, j, m, r, t), (a, e, g, j, n, P, s), (a, e, g, j, n, p, t), (a, e, g, j, n, q, s), (a, e, g, j, n, q, t), (a, e, g, j, n, r, s), (a, e, g, j, n, r, t), (a, e, g, j, o, p, s), (a, e, g, j, o, p, t), (a, e, g, j, o, q, s), (a, e, g, j, o, q, t), (a, e, g, j, 〇, t, s), (a, e, g, j, o, x, t), (a, e, g, k, m, p, s), (a, e, g, k, m, p, t), (a, e, g, k, m, q, s), (a, e, g, k, m, q, t), (a, e, g, k, m, r, s), (a, e, g, k, m, r, t), (a, e, g, k, n, p, s), (a, e, g, k, n, p, t), (a, e, g, k, n, q, s), (a, e, g, k, n, q, t), (a, e, g, k, n, r, s), (a, e, g, k, n, r, t), (a, e, g, k, o, p, s), (a, e, g, k, o, p, t), (a, e, g, k, o, q, s), (a, e, g, k, o, q, t)s (a, e, g, k, o, r, s) , (a, e, g, k, o, r, l), (a, e, g, 1, m, p, s), (a, e, g, I, m, p, t), (a, e, g, 1, m, q, s), (a, e, g, l, m, cj, t), e, g, I, m, Γ, s), (a, e, g, 1, m, i, t), (a, c, g, 1, n, p, s), (s, e, g, I, h, p, t), (a, e, g, 1, n, q, s), (a, e, g, 1, d, q, t), (a, e, g, 1, u, r, s), (a, e, g, 1, n, r, t), (a, e, g, 1, o5 p, s), (a, e, g, 1, o, p, 1), (a, e, g, 1, o, q, s), (a, e, g, 1, o, q, t), (a, e, g, 1, o, r, s), (a, e, g, 1, o, r, t), (a, e, h, j, m, p, s), (a, e, h, j, m, p, t), (a, e, h, j, m, q, s), (a, e, h, j, m, q, t), (a, e, h, j, m, r, s), (a, e, h, j, m, r, t), (a, e, h, j, n, p, s), (a, e, h, j, n, p, t), (a, e, h, j, n, q, s), (a, e, h, j, n, q, t), (a, e, h, j, n, r, s), (a, e, h, j, n, r, t), (a, e, h, j, o5 p, s), (a, e, h, j, o, p, t) , (a, e, h} ), o, q, s), (a, e, h, j; o, q, 1), (a, e, h, j, o, r, s), (a, e, h, j, o, r, t), (a, e, h, k, -12- 1314868 五、發明說明（11) P，s), (a, e, h, k, m3 p, t); (a, e, h, k, m, q, s), (a, e, h, k} m, q, t), (a, e5 h, k, m, r, s)} (a, e, h, k, m, r, t), (a, e, h, k, n, p, s), (a, e, h, k, n, p, l), (a, e, h, k, u, q, s), (a, e, h, k, n, q, t), (a, e, b, k, n, r, s), (a, e, h, k, n, r, t), (a, e, h, k, o, p, s), (a, e, h, k, o, p, t), (a, e, h, k, o, q, s), (a, e, h3 k, o, q, 1), (a； e, h, k, o, r, s), (a, e, h, k, o, r, t), (a, e, h, 1, m, p, s), (a, e, h, Is ms p, t), (a, e, h, 1, m, q, s), (a, e, h, I, m, q, t), (a, e, h, I, m, r, s), (a, e, h, l, m, t, t), (a, e, h, 1, n, p, s), (a, e, h, 1, n, p, t), (a, e, h, 1, n, q, s), (a, e, h, ], n, q, t), (a, e, h, 1, n, r, s), (a, e, h, 1, n, r, t), (a, e, h, 1, o, p, s), (a, e, h, ], o, p, t), (a, e, h, 1, o, q, s), (a, e, h, 1, o, qs t), (a, e, h, 1, o, r, s), (a, e, h, 1, o, i, t), (a, e, i, j, m, p, s), (a? e, i, j, m, p, t), (a, e, i, j, m, q, s), (a, e, i, j, m, q, t), (a, e, i, j, m, r? s), (a5 e, is j, m, r, t), (a, e, i, I j, n, p, s), (a, e, i, j, n, p, t), (a, e, i, j, n, q, s), (a, e, i, j, n, q, t), (a, e, i, j, n, r, s), (a, e, J i, j, n, r, t), (a, e, i, j, o, p, s), (a, e, i, j, o, p, t), (a, e, i, j, o, q, s), (a, e, i, j, o, q, t), (a, I e, i, j, o, r, s), (a, e, i, j, o, r, t), (a, e, i, k, m, p, s), (a, e, i, k, m, p, t), (a, e, i, k, m, q, s), f '(a，e, i，k，m, q，t)，（a，e，i, k，m, r, s), (a，e，i，k，m，r，t)，（a，e，i, k，n，p, s), (a，e，i, k, n， p, t), (a, e, i, k, n, q, s), (a, e, i, k, n, q, t), (a, e, i, k, n, r, s), (a, e, i, k, n, r, t), (a,* e, i, k，〇, p，s)，（a, e，i，k，〇’ p，t)，（a，e，i，k，〇, q，s)，（a，e，i，k，〇, q，t)，（a，e，i，k，〇, r，s)，（a， e, i, k, ο, t, t), (a, e, i, 1, m, p, s), (a, e, i, 1, m, p, t), (a, e, i, 1, m, q, s), (a, e, i, 1, m, q, 1), (a, e, i, 1, m, r, s), (a, e, i, 1, m, r, t), (a, e, i, 1, n, p, s), (a, e, i, 1, n, p, t), (a, e, i, 1, n, q, s), (a, e, i, 1, n, q, t), (a, e, i, 1, n, r, s), (a, e, i, 1, n, r, t), (a, e, i, 1, o, p, s), (a, e, i, 1, o, p, t), (a, e, i, 1, o, q, s), (a, e, i, 1, o, q, t), (a, e, i, 1, o, r, s), (a, e, i, 1, o, r, t), (a, f, g, j, m, p, s), (a, f, g, j, m, p, t), (a, f, g, j, m, q, s), (a, f, g, j, m, q, t), (a, f, g, j, m, r, s), (a, f, g, j, m, r, t), (a, f, g, j, n, p, s), (a, f, g, j, n, p, t), (a, fs g, j, n, q, s), (a, f, g, j, n, q, t), (a, f, g, j, n, r, s), (a, f, g, j, n, r, t), (a, f, g, j, o, p, s), (a, f, g, j, o, p, t), (a, f, g, j, o, q, s), (a, f, g, j, o, q, t), (a, f, g, j, o, r, s), (a, f, g, j, o, r, 1), (a, f, g, k, m, p, s), (a, f, gs ks m, p, t), (a, f, g, k, m, q, s), (a, f, g, k, m, q, t), (a, f, g, k, m, r, s), (a, f, g, k, m, r, t), (a, f, g, k, n, p, s), (a, f, g, k, n, p, t), (a, f, g, k, n, q, s), (a, f, g, k, n, q, l), (a, f} g, k, n, r, s)，（a，f，g, k，η, r，1)，（a，f，g，k, 〇, p，.s)，（a，f, g，k, 〇, p，t)，（a, i'，g，k，〇, q’s), (a，i; g，k’ o, q, l), (a, f, g, k, o, r} s), (a, f5 g, k, o, r, t), (a, f, g, 1, m, p, s), (a, f, g, 1, m, p, t), (a, f, -13- 1314868 五、發明說明（12) g, 1, m, q, s), (a, f, g, 1, m, q, t), (a, f, g, 1, m, i, s), (a, f, g, 1, m, r, 1), (a, f, g, 1, n, p, s), (a, f, g, 1, π, ρ, (a, iy g, n, s)? (a? f, g, 1, n5 Qj 1)} (a, f, g, 1, n, r, s), (a, t, g, 1, d, r, t), (a, f, g, 1, o, p, s), (a, f, g, 1, o, p, t), (a, f, g, 1, o, q, s), (a, f, g, 1, o, q, t), (a, f, g, 1, o, r, s), (a, f, g, 1, o, r, 1), (a, f, h, j, m, p, s), (a, f, h, j, m, p, t), (a, f, h, j, m, q, s), (a, f, h, j, m, q, t), (a, f, h, j, m, i, s), (a, f, h, j, m, r, t), (a, f, h, j, n, p, s), (a, f, h, j, n, p, t), (a, f, h, j, n, q, s), (a, f, h, j, n, q, t), (a, f, h, j, n, r, s), (a, f, h,.j, n, r, t), (a, f, h, j, o, p, s), (a, f, h, j, o, p, t), (a, f, h, j, o, q, s), (a, f, h, j, o, q, t), (a, f, h, j, o, r, s), (a, f, h, j, o, r, t), (a, f, h, k, m, p, s), (a, f, h, k, m, p, t), (a, f, h, k, m, q, s), (a, f, h, k, m, q, t), (a, f, h', k, m, r, s), <a, f, h, k, m, r, t), (a, I, h, k, d, p, s), (a, f, h, k, n, p, 1), (a, f, h, k, n, q, s), (a, f, h, k, n, q, t), (a, f, h, k, n, r, s), (a, f, h, k, n, r, t), (a, f, h, k, o, p, s), (a, f, h, k, o, p, t), (a, f, h, k, o, q, s), (a, f, h, k, o, q, t), (a, f, h, k, o, r, s), (a, f, h, k, o, i, t), (a, f, h, 1, m, p, s), (a, f, h, 1, m, p, t), (a, f, h, 1, m, q, s), (a, f, h, 1, m, q, t), (a, f, h, 1, m, r, s), (a, f, h, 1, m, r, t), (s, f> h, 1, n, p, s), (3, f, b, 1, n, p, t), (a, f, h, 1, n, q, s), (a, f, 1} n, (j, t), (a, f, h, 1, n, r, s), (a, f, h, 1, n, r, t), (a, f, h, 1, o, p, s), (a, f, h, 1, o, p, t), (a, f, h, 1, o, q, s), (a, f, h, 1, o, q, t), (a, f, h, 1, o, r, s), (a, f, h, 1, o, i, t), (a, f, i, j, m, p, s), (a, f, i, j, m, p, l), (a, f, i} j, m, q, s), (a, f, j, j, ni, q, t), (fl, f, i, j, in, r, s), (a, f, i, j, m, Tr t)? (a, f, i, j5 n, p, s), (a, f, i, j, n, p, 1), (a, f, i, j, n, q, s), (a, f, i, j, n, q, t), (a, f, i, j, n, i, s), (a, f, i, j, n, r, t), (a, f, i, j, o, p, s), (a, f, i, j, o, p, t), (a, f, i, j, o, q, s), (a, f, i, j, o, q, t), (a, f, i, j, 〇. r, s), (a, f, i, j, o, r, t), (a, f, i, k, m, p, s), (a, f, i, k, m, p, t), (a, f, i, k, m, q, s), (a, f, i, k, m, q, t), (a, f, i, k, m, r, s), (a, f, i, k, m, r, t), (a, f, i, k, n, p, s), (a, f, i, k, n, p, t), (a, f，i，k，n，q，s)，（a, f，i, k，u，q，t)，（a，f，i，k，n，r，s)，（a, f, i，k, n, r，t)，（a，i，k，〇，p， s), (a, f, i, k, 〇, p, t), (a, f, i, k, o, q, s), (a, f, i, k, o, q, t), (a, f, i, k, o, r, s), (a, f, i, k, o, i, 1), (a, f, i, 1, m, p, s), (a, f, i, 1, m, p, t), (a, f, i, 1, m, q, s), (a, f, i, 1, m, q, t), (a, f, i, 1, m, r, s), (a, f, i, 1, m, i, t), (a, f, i, 1, n, p, s), (a, f, i, 1, n, p, 1), (a, f, i, 1, n, q, s), (a, f, i, 1, n, q, t), (a, f, i, 1, η, t, s), (a, f, i, 1, n, r, t), (a, f, i, I, o, p, s), (a, f, i, 1, o, p, t), (a, f, i, 1, o, q, s), (a, f, i, 1, o, q, t), (a, f, i, 1, o, r, s), (a, f, i, 1, o, i, t), (b, d, g, j, m, p, s), (b, d,g, j, m, p, t), (b, d, g, j, m, q, s), (b, d, g, j, m, q, t), (b, d, g, j, m, t, s), (b, d, g, j, m, r, -14- 1314868 五、發明說明（13)''t), (b, d, g, j, n, p, s), (b, d, g, j, n, p, 1), (b, d; g, j5 n, q; s), (b, d, g, j, n, q, t), (b, d, g, j, n, r, s), (b, d, g, j, u, r, t), (b, d, g, j, o, p, s), (b, d, g, j, o, p5 t), (b, d, g, j, o, q, s), (b, d, g, j, 6, q, t), (b, d, g, j, o, r, s), (b, d, g, j, ο, t, t), (b, d, g, k, m, p, s), (b, d, g, k, m, p/t), (b, d, g, k, m, q, s), (b, d, g, k, m, q, t), (b, d, g, k, m, r, s), (b, d, g, k, m, r, t), (b, d, g,k, n, p, s), (b, d, g, k, n, p, t), (b, d, g, k, n, q, s), (b, d, g, k, n, q, t), (b, d, g, k, n, r, s),(b, d, g, 1c, n, r, t), (b, d, g, k, o, p, s), (b, d, g, k, o, p, t), (b, d, g, k, o, q, s), (b, d, g, k, o, q} t)s (b, d, g, k, o, x, s), (b, d, g, k, o, r, t), (b, d, g, 1, m, p, s), (b, d, g, 1, m, p, t), (b, d, g, 1, m, q, s), (b, d, g, 1, m, q, t), (b, d, g, 1, m, r, s), (b, d, g, 1, m, r, t), (b, d, g, 1, n, p, s), (b, d, g, 1, n, p, t), (b, d, g, 1, n, q, s), (b, d, g, 1, n, q, t), (b, d, g, ], n, r, s), (b, d, g, 1, n, r, t), (b, d, g, 1, o, p, s), (b, d, g, 1, o, p, t), (b, d, g, I, o, q, s), (b, d, g, 1, o, q, t), (b, d, g, 1, o, r, s), (b, d, g, 1, o, r, t), (b, d, h, j, m, p, s), (b, d, h, j, m, p, t), (b, a, h, j, m, q, s), .(b, d, h, j, m, q, t), (b, d, h, j, m, r, s), (b, d, h, j, m, r, t), (b, d, h, j, n, p, s), (b, d, h, j, n, p, t), (b, d, h, j, n, q, s), (b, d, h, j, n, q, t), (b, d, h, j, n, r, s), (b, d, h, j, n, r, t), (b, d, h, j, o, p, s), (b, d, h, j, o, p, 1), (b, d, h, j, o, q, s), (b, d, h, j, o, q, t), (b, d, h, j, o, rs s), (b, d, h, j, o, r, t), (b, d, h, k, m, p, s), (b, d, h, k, m, p, t), (b, d, h, k, m, q, s), (b, d, h, k, m, q, t), (b, d, h, k, m, r, s), (b, d, h, k, m, r, t), (b, d, h, k, n, p, s), (b, d, h, k, n, p, t), (b, d, h, k, n, q, s), (b, d, h, k, n, q, t), (b, d, h, k, n, i, s), (b, d, h, k, n, x, t), (b, d, h, k, o, p, s), (b, d, h, k, o, p, t), (b, d, h, k, o, q, s), (b, d, h, k, o, q, t), (b, d, h, k, o, r, s), (b, d, h, k, o, r, t), (b, d, h, 1, m, p, s), (b, d, h, I, m, p, t), (b, d, h, 1, m, q, s), (b, d, h, 1, m, q, 1), (b, d, h, 1, m, r, s), (b, d, h, 1, m, r, t), (b, d, h, 1, n, p, s), (b, d, h, 1, n, p, t), (b, d, h, 1, n, q, s), (b, d, h, 1, n, q, t), (b, d, h, 1, n, r, s), (b, d, h, 1, n, r, t), (b, d, h, 1, o, p, s), (b, d, h, l, o, p, t), (b, d, h, 1, o, q, s), (b, d, h, 1, o, q, t), (b, d, h, 1, o, x, s), (b, d, h, 1, o, r, t), (b, d, i, j, m, p, s), (b, d, i, j, m, p, t), (b, d, i, j, m, q, s), (b, d, i, j, m, q, t), (b, d, i, j, m, r, s), (b, d, i, j, m, r, t), (b, d, i, j, n, p, s), (b, d, i, j, n, p, t), (b, d, i, j, n, q, s), (b, d, i, j, n, q, t), (b, d, i, j, n, r, s), (b, d, i, j, n, r, t), (b, d, i, j, o, p, s), (b, d, i, j, o, p,-t), (b, d, i, j, o, q, s), (b, d, i, j, o, q, t), (b, d, i, j, o, r, s), (b, d, i, j, o, r, t), (b, ds i, k, m, p, s), (b, d, i, k, m, p, t), (b, d, i, k5 m, q, s), (b, d, i, k, m, q, t), (b, d, i, k, m, r, s), (b, d, i, k, m, , ·. -1 5.- 1314868
五、發明說明（14) . . r, t), (b, d, i, k, n, p, s), (b, d, i, k, n, p, t), (b, d, i, k, n, q, s), (b, d, i, k, n, q, t), (b, d, k, η, t, s), (b, d, i, k, n, r, t), (b, d, i, k, o, p, s), (b, d, i, k, o, p, t), (b, d, i, k, o, q, s), (b d, i, k, o, q, 1), (b, d, i, k, o, r, s), (b, d, i, k, o, r, t), (b, d, i, 1, m, p, s), (b, d, i, 1, m, t), (b, d, i, 1, m, q, s), (b, <3, i, 1, m, q, t), (b, d, i, 1, m, r, s), (b, d, i, 1, m, r, t), (b, d, i, и, p, s), (b, d, i, 1, n, p, t), (b, d, i, 1, n, q, s), (b, d, i, 1, n, q, t), (b, d, i, 1, n, r, s), (b, d i，1，n，r, t)，（b，d，I，1，〇，p，s)，（b，d，1，1, 〇，p，t)，（b，d，i，1，〇，q，s)，（b，d，i，I，〇，q, t)，（b d, i, 1, o, r, s), (b, d, i, 1, o, r, t), (b, e, g, j, m, p, s), (b, e, g, j, m, p, t), (b, e, g, j, m, q s), (b, e, g, j, m, q, t), (b, e, g, j, m, r, s), (b, e, g, j, m, r, t), (b, e, g, j, n, p, s), (b, e, g j, n, p, t), (b, e, g, j, n, q, s), (b, e, g, j, n, q, t), (b, e, g, j, n, r, s), (b, e, g, j, n, r, t), (b e, g, j, 〇, p, s), (b, e, g, j, o, p, t), (b, e, g, j, o, q, s), (b, e, g, j, o, q, t), (b, e, g, j, o, i, s) (b, e, g, j, o, r, t), (b, e, g, k, m, p, s), (b, e, g, k, m, p, t), (b, e, g, k, m, q, s), (b, e, g, k m, q, t), (b, e, g, k, m, r, s), (b, e, g, k, m, r, t), (b, e, g, k, u, p, s), (b, e, g, k, n, p, t), (b e, g, k, n, q, s), (b, e, g, k, n, q, t), (b, e, g, k, n, r, s), (b, e, g, k, n, r, t), (b, e, g, k, o, p s) , (b, e, g, k, o, p, t), (b, e, g, k, o, q, s), (b, e, g, k, o, q, t), (b, e, g, k, o, r, s), (b, e, g к, o, r, t), (b, e, g, 1, m, p, s), (b, e, g, 1, m, p, t), (b, e, g, ], m, q, s), (b, e, g, 1, m, q, 1) (b, e, g, 1, m, r, s), (b, e, g, 1, m, r, t), (b, e, g, 1, n, p, s), (b, e, g, 1, n, p, t), (b, e, g, 1, n q, s), (b, e, g, 1, n, q, 1), (b, e, g, 1, n, i, s), (b, e, g, 1, n, r, t), (b, e, g, 1, o, p, s), (b, e, g 1, o, p, t), (b, e, g, 1, o, q, s), (b, e, g, 1, o, q, t), (b, e, g, 1, o, r, s), (b, e, g, 1, o, r, t), (b e, h, j, m, p, s), (b, e, h, j, m, p, t), (b, e, h, j, m, q, s), (b, e, h, j, m, q, t), (b, e, h, j, m r, s), (b, e, h, j, m, r, t), (b, e, h, j, n, p, s), (b, e, h, j, n, p, t), (b, e, h, j, n, q, s), (b, e, h j, u, q, t), (b, e, h, j, n, r, s), (b, e, h, j, n, r, 1), (b, e, h, j, o, p, s), (b, e, h, j, o, p, t), (b e, h, j, o, q, s), (b, e, h, j, o, q, t), (b, e, h, j, o, i, s), (b, e, h, j, o, r, t), (b, e, h, k, m, p .s), (b, e, h, k, m, p, t), (b, e, h, k, m, q, s), (b, e, h, k, m, q, t), (b, e, h, k, m, r, s), (b, e h, k, m, r, t), (b, e, h, k, n, p, s), (b, e, h, k, n, p, t), (b, e, h, k, n, q,*s), (b, e, h, k, n, q t) , (b, e, h, k, n, r, s), (b, e, h, k, n, r, t), (b, e, h, k, o, p, s), (b, e, h, k, o, p, t), (b, e, h k, o, q, s), (b, e, h, k, o, q, t), (b, e, h, k, o, r, s), (b, e, h, k, o, r, t), (b, e, h, 1, m, p, s) (b, e, h, 1, m, p, t), (b, e, h, 1, m, q, s), (b, e, h, 1, m, q, 1), (b, e, h, 1, m, r, s), (b, e, h, I -16- 1314868 五、發明說明（15) mt r, 1), (b? e, h, 1, n, p, s), (b5 e, h, 1, u, p, t), (b, e, h, 1, n, q, s), (b, e, h, 1, n, q, t), (b, e; h，1，n，r，s)，（b，e，h，1，n，r，t)，（b，e，h，1，〇，p，s)，（b，e，h，I，〇，p，1)，（b，e，h’ 3，〇，q, s)， (b，e，h，1，o, q，t)，（b，e，h，1，〇, r，s)，（b，e，h，1，〇, I，1)，（b，e，i，j，m，p，s)，（b，e，i，j，m， P，t)，（b，e，i，j，m，q，s)，(b，e，i，j，in, q，t)，(b，e，i，_j, m, t，s), (b, e, i’ j，m，r，t), (b’ e, i’ j，n，p，s)，（b，e，i，j，n，p，t)，（b，e，i，j，n，q，s)，（b，e，i，j，1】，q，t)，（b，e，i，j，n，r，s)，（b，e， i, j, n, r, t), (b, e, i, j, o, p, s), (b, e, i, j, o, p, t), (b, e, j, j, o, q, s), (b, e, i, j, o, q, t), (b, e，i，j, 〇, r，s)，（b，e，i，j，〇, r，t)，（b，e，i，k，m，p，s)，（b，e，i，k, m, p，t), (b，e，i，k，m，q， s)，（b，e，i，k，m’ q, t)，（b，e, i，k，m，r, s)，（b，e，i，k，m，r，t)，（b，e, i，k，n，p，s)，（b，e，i， k, n, p, t), (b, e, i, k, n, q, s), (b, e, i, k, n, q, t), (b, e, i, k, n, r, s), (b, e, i, k, n, r, t), (b, e，i，k，〇, p，s)，（b，e，i，k，〇, p, t)，（b，e，i，k，〇, q，s)，（b，e，i，k，〇, q，t)，（b，e，i，k，〇, r，s)， (b，e，i，k，〇, r, t)，（b，e，i，1，m，p，s)，（b，e，i，1，m，p，t)，（b，e，i，1，m，q，s)，（b，e，i，1，m， q, t), (b, e, i, 1, m, r, s), (b, e, i, 1, m, r, t), (b, e, i, 1, n, p, s), (b, e, i, 1, n, p, t), (b, es i, l, n, q, s), (b, e, i, 1, n, q, t), (bs e, i, ], n, i, s), (b, e, i, 1, n, r, t), (b, e, i, ], o, p, s), (b, e, i, 1, o, p, t), (b, e, i, 1, o, q, s),'(b, e, is 1, o, q, t), (b, e, i, 1, o, r, s), (b, e, i, 1, ο, i, t)s (b, f, g, j, m, p, s), (b, f, g, j, m, p, t), (b, f, g, j, m, qs s), (b, f, g, j, m, q, t), (b, f, g, j, m, r, s)» f. g> h Hi, r, t), (b, f, g, j, n, p, s), (b, f, g, j, n, p, t), (b, f, g, j, n, q, s), (b, f, g, j, n, q, t), (b, f, g, j, n, r, s), (b, f, g, j, n, r, t), (b, f, g, j, o, p, s), (b, f, g, j, o, p, t), (b, f, g, j, 〇, q> s), (b, f, g, j, o, q, t), (b, f, g, j, o, r, s), (b, f, g, j, o, r, t), (b, f, g, k, m, p, s), (bs f, g, k, m, p, t), (b, f, g, k, m, q, s), (b, f, g, k, m, q, t), (b, f, g, k, m*, r, s), (b, f, g, k, m, r, t), (b, f, g, k, n, p, s), (b, f; g, k, n? p? t), (b, f, g, k, n, q, s), (b, Ϊ, g, k, n, q, t), (b, j f, g, k, li, r, s), (b, f, g, k, n, r, t), (b, f, g, k, o, p, s), (b, f, g, k, o, p, t), (b^f, g, k, o, q, s) , (b, f, g, k, o, q, t), (b, f, g, k, ο, t, s), (b, f, g, k, o, r, t), (b, f, g, 1, m,.p, s), (b, f, g, 1, m, p, t), (b, f, g, 1, m, q, s), (b, f, g, 1, m, q, t), (b, f, g, ], m, r, s), (b, f, g, ], m, r, t), (b, f, g, I, n, p, s), (b, f, g, 1, r, p, t), (b, f, g, ], n, q, s), (b, f, g, 1, n, q, (b, f, g, 1, n, r, s), (b, f, g, 1, η, T, t)s (b, f, g5 1, o, p, s), (b, f, g, 1, o, p, l), (b, f, g, 1, o, q, s), (b, f, g, 1, o, q, t) , (b, f, g, 1, o, r, s), (b, f, g, 1, o, r, l), (b, f, h, j, m, p, s), (b, f, h, j, m, p, t), (b5 is h, j, m, q3 s), (b, j, m} q; t), (b, f, h, j, m, r, s), (b, f, h, j, m, t? t)5 (b, f, h, j, n} p, s), (b, -17- 1314868 五、發明說明（16) f, h? j, η, ρ, t), (b, f, h5 j, n； q, s), (b, f, h, j, n, q, t), (b, f, h, j, n, x, s), (b, f, h, j, u, r, 1),-(b, f, h, j, o, p, s), (b, f, h, j, o, p, t), (b, f, h, j, o, q, s), (b, f, h, j, o, q, t), (b, f, h, j5 o, r, s) , (b, f, h, j? o, r, l), (b, f, h, k, m, p, s), (b, f, h, k, m, p, t), (b, f, h, k, m, q, s), (b, f, h, k, m, q} t), (b, f, h5 k, m, r, s), (b, f, h, k, m, r, t), (b, f, h, k, n, p, s), (b, f, h, k, u, p, t), (b, f, h, k, n, q, s), (bs f, h, k, n, q, t), (b, f, h, k, n, r, s), (b, f, h, k, η, t} t), (b, f, h, k, o, p, s), (b, f, h, k, o, p, t), (b, f, h, k, o, q, s), (b, f, h, k, o, q, t), (b, f, h, k, ο, i, s), (b, f, h, k, o, r, t), (b, f, h, 1, m, p, s), (b, f, h, 1, m, p, t), (b, f, h, 1, m, q, s), (b, f, h, 1, m, q, t), (b, f, h, 1, m, r, s), (b, fs h, 1, m, r, t), (b, f, h, 1, n, p, s), (b, f, h, 1, n, p, t), (b, f, h, 1, n, q, s), (b, f, h, 1, n, q, t), (b, f, h, 1, n, r, s), (b, f, h, 1, n, r, t), (b, f, h, 1, o, p, s), (b, f, h, 1, o, p, t) , (b, f, h, 1, o, q, s), (b, f, h, 1, o, q, t), (b, f, h, 1, o, r, s), (b, f, h, 1, o, r, t), (b, f, i, j, m, p, s), (b, f, i, j, m, p, t), (b, f, i, j, m, q, s), (b, f, i, j, m, q, t), (b, f, i, j, m, r, s), (b, f, i, j, m, r, t), (b, f, i, j, n, p, s), (b, f, i, j, n, p, t), (b, f, i, j, n, q, s), (b, f, i, j, n, q, t), (b, f, i, j, n, rs s), (b, f, i, j, n, r, t), (b, f, i, j, o, p, s), (b, f, i, j, o, p3 t), (b, f, i, j, o, q, s), (b, f, i, j, o, q, t), (b, f, i, j, o, r, s), (b, f, i, j, o, r, t), (b, f, i, k, m, p, s), (b, f, i, k, m, p, t), (b, f, i, k, m, q, s), (b, f, i, k, m, q, t), (b, f, i, k, m, r, s), (b, f, i, k, m, r, t), (b, f, i, k, n, p, s), (b, f, i, k, n, p, t), (b, f, i, k, n, q, s), (b, f, i, k, n, q, t), (b, f, i, k, n, r, s), (b, f, i, ' k, n, rt t), (b, f, i, k, o, p, s), (b, f, i, k, o, p, t), (b, f, i, k, o, q, s), (b, f, i, k, o, q, t), (b, f, i, k, o, r, s), (b, f, i, k, o, r, t), (b, f, i, 1, m, p, s), (b, f, i, 1, m, p, t), (b, f, i, 1, m, q, s), (b, f, i, 1, m, q, t), (b, f, i, 1, m, r, s), (b, f, i, 1, m, r, t), (b, f, i, I, n, p, s), (b, f, i, 1, u, p, t), (b, f, i, 1, n, q, s), (b, f, i, 1, n, q, t), (b, f, i, 1, u, r, s), (b, f, i, 1, n, r, t), (b, f, i, 1, o, p, s), (b, f, i, 1, o, p, t), (b, f5 i, 1, o, q, s), (b, f, i, 1, o, q, t), (b, f, i, 1, o, r, s), (b, f, i, 1, o, h t), (c, d; g, j, m, p, s), (c, d, g, j, m, p, t), (c, d, g, j, m, q, s), (c, d, gs j, m, q, t), (c, d, g, j, m, t, s), (c, d, g, j, m, r, t), (c, d, g, j, n, p, s), (c, d, g, j, n, p, t), (c, d, g, j, n, q, s), (c, d, g, j, n, q, t), (c, d, g5 j, n, r, s), (c, d, g, j, n, r, t), (c5 d, g, j, o, p, s), (c, d, g, j, o, P，〇> (c, d, g5 j, o, q, s), (c, d, g, j, o, q, t), (c, d, g, j3 o, rs s), (c, d, g, j, o, r, t), (c, d} g, .k, m, p} s), (c} d; g, k, m, p, t), (c, d, g, k, m, q, s), (c, d, g, k, m, q, t), (c, d, g, k, m, r, s), (c, d, g, k, m, r, t)s (c, d? g, k, n, p, s), (c, d, g, k, n, p, t), (c, d, g, k, n, q, s), (c, d, g, -18- ' 1314868 五、發明說明（17) k, η, q, t), (c, d, g, lc, n, r, s), (c, d, g, k, η, t, t), (c, d, g, k, o, p, s)5 (c, d, g, k, o, p, t), (c, d, g, k, o, q, s), (c, d, g, k, o, q, t), (c, d, g, k, o, r, s)5 (c, d, g, k, ο, t, t), (c, d, g, ], m, p, s), (c, d} g, 1, m, p, t), (c, d, g, 1, in, q, s), (c, d, g, \} m3 q, t), (c, d, g, 1, m, r, s), (c, d, g, l, m, i5 t), (c, d, g, 1, n, p, s), (c, d, g, 1, n, p, 1), (c, d, g, 1, n, q, s), (c, d, g, 1, n, q, t), (c, ds g, 1, n, r, s), (c, d, g, 1, n, r, t), (c, d, g, 1, o, p, s), (c, d, g, 13 o, p, t), (c, d, g, 1, o, qs s), (c, d, g, 1, o, q, t), (c, d, g, 1, o, rs s), (c, d, g, 1, o, r, t), (c, d, h, j, m, p, s), (c, d, h, j, m, p, t), (c, d, h, j, m, q, s), (c, d, h, j, m, q, t), (c, d, h, j, m, r, s), (c, d, h, j, m, r, t), (c, d, h, j, n, p, s), (c, d, h, j, n, p, t), (c, d, h, j, ns q, s), (c, d, h, j, n, q, t), (c, d, h, j, n, rs s), (c, d, h, j, n, r, t), (c, d, h, j, o, p, s), (c, d, h, j, o, p, t), (c, d, h5 j, o, q, s), (c, d, h, j, o, q, t), (c, d, h, j, o, r, s), (c, d, h, j, o, r, t), (c, d, h, k, m, p, s), (c, d, h, k, m, p, t), (c, d, h, k, m, q, s), (c, d, h, k, m, q, t), (c, d, h, k, m, r, s), (c, d, h, k, m, r, t), (c, d, h, k, n, p, s) , (c, d, h, k, n, p, t), (c5 d, h, k, n, q, s), (c, d, h, k, n, q, t), (c, d, h, k, n, r, s), (c, d, h, k, n, r, t), (c, d, h, k, o, p, s), (c, d, h, k, o, p, t), (c, d, h, k, o, q, s), (c, d, h, k, o, qs t), (c，d，h，k, 〇，r，s), (c，d，h, k，〇，r, t), (c，d, h，1，m，p，s)，（c，d，h，1，m, p，t), (c，d，h, 1，m，q, s), (c, d, h, 1, m, q, t), (c, d, h, 1, m, r, s), (c, d, h, 1, m, r, t)i (c, d, h, 1, n, p, s), (c, d, h, 1, n, p, t), (c, d, h, 1, n, q, s), (c, d, h, 1, n, q, t), (c, d, h, 1, n, r, s), (c, d, hs 1, n, r, 1), (c，d，h，1，〇，p，s)’（c，d，h’ I, o, p, t), (c，d, h, 1, 〇，q, s), (c, d, h，1，〇，q, t), (c，d, h’ 1, o, r, s), (c, d, h, 1, o, r, t), (c, d, i, j, m, p, s), (c, d, i, j, m, p, t), (c, d, i, j, m, q, s), (c, d, i, j, m, q, t), (c, d, i, j, m, r, s), (c, d, i, j, m, r, t), (c, d, i, j, n, p, s), (c, d, i, j, n, p, t), (c, d，i» j，n，q，s)，（c，d，i，j，ii，q，t)，（c，d，i，j，n，r，s)，（c，d，i，j’ ή，r，t)，（c, d, i，j，〇，p，s)， (c, d, i, j, o, p, t), (c, d, i, j, o, q, s), (c, d, i; j, o, q, t), (c, d, i, js o, r, s), (c, d, i, j, o, r,t) , (c, d, i, k, m, p, s), (c, d, i, k, m, p, t), (c, d, j, k, in, q, s), (c, d, i, 3c, m, qf t), (c, d, i, k, m, r, s), (c, d, i, k, m, r, t), (c, d, i, k, n, p, s), (c, d, i, k, n, p, t), (c, d, i, k, u, q, s), (c, d, i，k, n, q，I)，（c，d，i，k，1】，r, s)，（c, d，i，k，n，r，t)，（c，d, i，k，o, p，s)，<c，d，i，k，〇, p，t)， (c, d，i，k，〇，q，s)，（c，d，i, 1c, 〇，q，t)，（c，d，i，kj 〇，r，s)，（c，d，i，lc，〇，r，1)，（c，d，]，ιώ， p，s)，（c，d，i，1，m，p，t)，（c，d，i，1，m，q，s)，（c，d，i，1，m, q，t)，（c，d，i，1，m，r, s)，（c，d，i， l, m, r} t), (c, d, i, 1, n, p, s), (c, d, i, 1, n} p, 1), (c, d, i, 3, n, q, s), (c, d, i, 1, n, q, t), (c, d, -19- 1314868 五、發明說明（18) • · i5 1, η, Γ, s), (c, d; i, 1, u, r, t), (c, d, i, ], o, p, s), (c, d, i, 3, o, p, t), (c, d, i, ], o, q, s), (c, ( d, i} 1, o, q, 1), (c, d, i, 1, o, r, s), (c, d, i, 1, ο, t, t), (c, e, g, j, m, p, s), (c, e, g, j, mf p, 1), (c，e，g，j，in, q，s)，(c，6，g，j，m，q，t)，(c，e，g，j，m，r) s)，(c, e, g，j，m, r, t), (c，e，g, j，n, p3 s), (cs e, g, j, n, p, t), (c, e, g, j, n, q, s), (c, e, g, j, n, q, t), (c, e, g, j, n, r, s), (c, e, g, j, n, r, t), (c, e, g, j, o, p, s), (c, e, g, j, o, p, t), (c, e, g, j, o, q, s), (c, e, g, j, o, q, t), (c, e, g, j, 〇, i, s), (c, e, g, j, o, r, t), (c, e, g, k, m, p, s), (c, e, g, k, m, p, t), (c, e, g, k, m, q, s), (c, e, g, k, m, qs t), (c, e, g, k, m, r, s), (c, e, g, k, m, r, t), (c, e, g, k, n, p, s), (c, e, g, n, p, 1), (c, e, g, k, n, q, s), (c, e, g, k, n, q, t), (c, e; g, k, j], r, s), (c, e, g, k, d, t, t), (c, e, g, k, o, p, s), (c, t, g, k, o, p, t), (c, e, g, k, o, q, s), (c, e, g, k, o, q, t), (c, e, g, k, o, r, s) , (c, e, g, k, o, r, t), (c, e, g, 1, m, p, s), (c, e, g, 1, m, p, t), (c, e, g, 1, m, q, s), (c, e, g, l, ms q, t), (c, e, g, 1, m, r, s), (c, e5 g, ], m, r, t), (c, e, g, 1, n, p, s), (c, e, g, 1, n, p, t), (c, e, g, 1, n, q, s), (c, e, g, 1, n, q, t), (c, e, g, 1, n, r, s), (c, e, g, 1, n, r, t), (c, e, g, 1, o, p, s), (c，e，g, 1, 〇, p，t), (c，e，g, 1，o, q，s)，（c, e, g, 1，〇, q, t)，（c, e，g，】，〇, r，s), (c，e, g, 1，〇， r, t), (c, e, h, j, m, p, s), (c, e, h, j? m, p, t), (c, e, h, j, m, q, s), (c, e, h, j, m, q, l), (c, e, h, j, m, r, s), (c, e, h, j, m, r, t), (c, e, h, j, n, p, s), (c, e, h, j, n, p, t), (c, e, h, j, n, q, s), (c, e, h, j, n, q, t), (c, e, h, j, n, r, s), (c, e, h, js n, r, t), (c, e, h, j, o, p, s), (c, e, h, j, o, p, t) ，（c，e，h，j，〇，q，s)，（c，e，h，j，〇，q，t)，（c，e，h，j，〇，r，s)，（c，e，h，j，〇，r，t)，（c，e，h，k, m, p, s), (c, e, h, k, m, p, t), (c, e, h, k, m, q, s), (c, e, h, k, m, q, t), (c, e, h, k, m, x, s), (c, e, h, k, m, r, t), (c, e, h, ks n, p, s), (c, e, h, k, n, p, 1), (c, e, h, k, n, q, s), (c, e, h, k, n，q，t), (c, e，h, k，n，r, s)，（c，e，h，k，li’ r，t)，（c，e，h，k，〇, p，s)，（c，e，h，k，〇, p，t)，（c， e, hs k, o, q, s), (c, e, h, k, o, q, t), (c, e, h, k, o, r, s), (c, e, h, k, o, r, t), (c, e, h, 1, m, p, s), (c, e, h, 1, m, p, t), (c, e, h, 1, m, q, s), (c, e, h, I, m, q, 1), (c, e, h, 1, m, r, s), (c, e, h,. 15 m, r, t), (c; e, h, 1, n, p? s), (c, e, h, 3, n, p, t), (c, e, h, 1, n, q, s), (c, e, h, 3, n, q, t), (c, e, h, 1, n, r, s), (c, e, h, 1, n, r, l), (c, e, h, ls o, ps s), (c, e, h, 1, o, p, t) *(c, e, h, 1, o, q, s), (c, e} h, 1, o, q, t), (c, e5 h, 1, o, r, s), (c, e, h, 1, o, r, t), (c, e, i, j, m, p, s), (c, e, i, j, m, P，t)? (c, e, i, j, m, q, s), (c, e, i, j, m, q, t), (c, e, i, j, m, i, s), (c, e, i, j, m, r, t),'(c} e, i} j! A，P：> s)，（c，e，i, j, ii，p, l), (c，e，i，j,】i, q, s), (c, e, i, j, l], q，t), (c, e，i’ j, ii’ r, s), (c, -20- 1314868 五、發明說明（19) i, j, u, r, 1), (c, e, i, j, o, p, s), (c, e, i, j, o, p, t)5 (c, e, i, j, o, q, s), (c; e, i; j, o, q, t), (c, e, i, j, os r, s), (c, e, i, j, o, r, t), (c, e, i, k, m, p, s), (c, e, i, k, m, p, t), (c, e, i, k, m, q, s), (c, e, i, k, m, q, t), (c, e, i, k, m, r, s), (c, e, i, k, m, i, t), (c, e, i, k, n, p, s), (c, e, i, k, u, p, l), (c, e, i, k, n, q, s), (c, e, i; k, n, q, t), (c, e, i, k, n, r, s), (c, e, i, k, n, r, t), (c, e, i, k, o, p, s), (c, e, i, k, o, p, t), (c, e, i, k, o, q? s), (c, e, i, k, o, q, t), (c, e, i, ks ο, t, s), (c, e, i, k, o, r, t), (c, e, i, 1, m, p, s), (c, e, i, 1, m, p, t), (c, e, i, 1, ms q, s), (c, e, i, 1, m, q, i), (c, e? i, 3, m, r, s), (c? e? i, 1, m, xf t), (c? e, i, ], n, p, s), (c, e, i, ], n, p, t), (c, e, i, 1, ns q, s)，（c，e，i，1，n，q, t)，（c，e, i，1，n，r, s)，（c，e，i，]，n，·!*’ t)，（c，e，i，1’ 〇，p，s)，（c，e，i，]，〇， p，t)，（c，e，i，1，〇, q，s)，（c，e，i，1，0, q，t)，（c, e, i，]，〇, r，s)，（c，e，i，1，〇, r，t)，（c，f，g，j， m, p, s), (c, f, g, j, m, p, t), (c, f, g, j, m, q, s), (c, f, g, j, m, q, t), (c, f, g, j, m, r, s), (c, f，g，J，m，r，t)，（c，f，g，j, li, p，s)，（c, f, g, j, n, p’t), (c, f’ g，j, n，q, s), (c，f’ g, j，d, q，t), (c，f，g» j，n，r，s)，（c, f，g, j, ii，r，t)，（c, f, g, j, o, p，s), (c，f，g, j, o, p, t)，（c, f, g, j, 〇，q， S)，（c，f, g，j’ 〇, q, 0,（c，f，g，j，〇, r，s)，（c，f，g，j’ 0, r，t)，（c，f，g，k，m，p，s)，（c，f，g，k， in, p, t), (c, f, g, k, m, q, s), (c, f, g, k, m, q, t), (c, f, g, k, m, r, s), (c, f； g, k, m, r, t), (c, f, g, k, n, p, s), (c, f, g, k, n, p, t), (c, f, g, k, n, q, s), (c, f, g, k, n, q, t), (c, f, g, k, n, r, s) ，（c，f，g，k，n，r，t)，（c，f，g，k，〇, p，s)，（c，f，g，k，〇, p，t)，（c，f, g，k，〇, q，s)，（c，i，g，k， o, q, t), (c, f, g, k, o, r, s), (c, f, g, k, o, r, t), (c, f, g, 1, m, p, s), (c, f, g, 1, m, p, t), (c, f, g, I, m, q, s), (c, f, g, I, m, q, t), (c, f, g, 3, m, x, s), (c, f, g, ], m, r, t), (c, f, g, 1, n, p, s), (c，f，g，1，n，p，t)，（c, f，g，1，n，q, s)，（c, f，g，1，11，q，t), (c，f，g，1，II，r，s), (c，f，g，1，n，r, t) ，（c，f，g，1, 〇, p，s)，（c, f，g，1，〇, p’t)，（c，f，g，1，〇, q，s)，（c，f，g，1，0, q，t)，（c，f，g，I，〇, r, s), (c, f, g, 1, ο, T, t), (c, fs h, j, m, p, s), (c, f, h, j, m, p, t), (c, f, h, j, m3 q, s), (c, f, h, j, m, q, t), (c, f, h, j, m, r, s), (c, f, h, j, m, r5 l), (c, f, h, j, n, p, s), (c, f, h, j, η, ρ» t), (c, f, h} j, n, q, s), (c, f, h, j, n, q, t), (c, f, h, j, n, r, s), (c, f, h, j, n, r, t), (c, f, h, j, o, p, s), (c, f, h, j, o, p, t), (c, f, h5 j, o, q, s), (c, f5 h, j, o, q, t), (c, f, h, j, o, r, s), (c, f, h, j, o, r, t), (c, f, h, k, in, p, s), (c, f, h, k, m, p, 1), (c, f, h, k, m, q, s)3 (c, f, h, k, m, q, t), (c, f, h, k, m, r, s), (c, f, h, k, mt r, t), (c, f, h, k, n, p, s), (c, f, h, k, n, p, t), (c, f, h, k, n, q, s), (c, f, h, k, ii, q, t)} (c, f, b, k, n, r, s), (c, f; h, k} n, i, l)5 (c, f, h, k, o, p, s), (c, f, h,· k, o3 p, -21 - 1314868 五、發明說明（20) 0,（C，f，h，k，0, q，s)，（C，f，11，k，0, q，t)，（c，f, h，k，〇’ r，s)，（c，i’，h，k，0, 1·，〇,（C，i，h’ 1’ m» P，s〉，（c，f，h，1，m，p» t), (c，f，红，1，m，q，s)，（c，f，h, ]，m，q，t)，（c，f，h，1，m，r，s)，（c， f，h’ 1, m, r，t)，（c’ f，h，1，n, p，s)，（c，f，h，1，n, p，t)，（c, f，h，1，n，q，s)，（c，f，h，1，11，q，t)’ (c，f，h，1，n，r, s)，（c, f, h, 1，n，r，t)，（c，f，h，1，〇, p，s)，（c，f，h，l，〇, j)，t)，（c，f，h，1，〇, q， s)> (c, f, h, 1, o7 q, t), (c, f, 1» 〇> r, s), (c, f, h, 1, o, r, t), (c, f, i, j, m, p, s), (c, f, i, j, m, P，0,（c，i，i, j，m，q，s)，（c，f，i，j，m，q，t)，（c，f，i，j，m，r，s)，（c，f，i，j，m’ r，t)，（c，f，i，j， n，P，s)，（c，f，i，j，n，p, 〇,（c，f，i，j，n，q，s)，（c，（，i，j，u，屮 （c，f，i，j，n，r，s)，（c，尤，至， j, u，r, t)，（c, f，i，j, 〇, P，s)，（c，尤，趴 j，〇, P，Ο，（c，艾，i，九 0，s)，（c，L 至，』，〇，1)，（C，& 〇> r, s), (c, f, i, j> 〇> t), (c, f» ij k, in, p, s), (c# f, i, k, m, p, t), (c, f, i, k, m, q, s), (c, f，i，k，m’ q，t), (c’ f，i, k, m，ϊ，s), (c，f，i，k，m，r，1)，（c，^ i，、n，P，s)，（c，（，i，k，n，p，t)’ (c, f, i, k, n, q, s), (c, f, i, k, n, q, 〇, (c, f, i, k, n, r, s), (c, f, i, k, η, t, t), (c, f, i, k, o, p, s)，（c，f，i，k, 〇, p, t)，（c，f，i，k, 〇, q，s)，（c，Hk，〇, q，t), (c，f，i，k，〇, r，s)，（c，f，i，k，〇， r，t)，（c，f，i，1，m，p，s)，（c，i，1，m，P，0，（c，尤，i，1，m，*1，s)，（c，t i，】，m，q，t)，（c，尤，支，1’ m，I，s), (c，f，i，1，m，r，t)，（c，f，i，】，d, p，s)，（c，f，i，1，n，p，t)，（c，f，i, 1，n，q，s)，（c, f, i, n* q. t), (c, f, i, 1, d, r, s), (c, f, i, 1, n, r, t), (c, f, i, 1, o, p, s), (c, f, i, 1, o, p, t), (c, f, i, I 〇, q, s)，（c，f, i，1，〇, q，〇, (c，f，i，U 〇, r’ s)’（c，f’ i, 1，〇, L 0. . ·· . 本發明之錠劑如下示之實驗例之記載，顯示優良之光安 定性。且即使主藥量多，亦可製成壓縮且具充分硬度而易 於服用之錠劑。 投予量依疾病之狀態、投予路徑、患者年齡、或體重而 異’但投予成人時，每日較佳投予約120 0mg~約1 8 00mg。 由於1日投予3回，1回投予量爲400mg〜600mg，較佳服 用2個主藥含量爲2〇〇rag~300mg之錠劑。 以下列舉實施例及試驗例詳細說明本發明，但本發明不 嗔於此。 -22- 1314868 五、發明說明（21) 實施例 實施例1 匹爾棻尼酮錠劑之製法 在匹爾棻尼酮2000g中加入乳糖560g及羧甲基纖維素 鈣50g，調製成混合粉末，將其置入流動層造粒機，噴霧 含有羥丙基纖維素60g之5重量％之水溶液，進行流動層 造粒，製得顆粒。對所得之顆粒加入5.6重量％之羧甲醚 鈣與1.1重量％之硬脂酸鎂，予以混合、打錠（13kN)，製 得匹爾棻尼酮素錠（12.0x6.Omm、285mg/錠，每錠含有 200mg之匹爾棻尼酮）。 使用高速包覆機，將含有羥丙基甲基纖維素66.7g、檸 檬酸三乙酯6.7g、及氧化鈦26. 6g之10重量％之水系包衣 液，以對上述匹爾棻尼酮素錠爲lOmg/錠包覆，製得目的 之匹爾棻尼酮錠劑。 每錠之組成如下。 -23- 1314868 五、發明說明（22) 表1 成分名 成份量 備註 匹爾薬尼酮 200.Omg 乳糖 56.Omg 羧甲基纖維素鈣 20.Omg 內添加5.Omg，外添加15.Omg 羥丙基纖維素 6. Omg 硬脂酸鎂 3. Omg 匹爾棻尼酮素錠計 285.0rag 羥丙基甲基纖維素2910 6.67mg 氧化鈦 2.66mg 檸檬酸三酯 0.67mg 硬脂酸鎂 微量 0.02rag 滑石 微量 0.02ms 包衣層計 lO.OOmg 合計 295. Omg 實施例2 曝光試驗 對將匹爾棻尼酮粉碎品約500mg裝入透明SP(條紋包裝 ，Striped Package)後，施以熱癒合之「匹爾薬尼酮原藥 j 、將匹爾棻尼酮粉碎品約300nig以靜壓縮機打錠之「匹 爾棻尼酮Μ縮成形品」、實施例1所得之「匹爾棻尼酮素 錠」、及實施例1所得之「匹爾棻尼酮錠劑」，以下列之 條件進行曝光試驗。結果如表2所示。 --- -24- 1314868 五、發明說明（23) (試驗條件） 光照射裝置：光安定性試驗裝置（LTL400 -D5)(納加諾科 學機械製作所） 螢光燈：色比較•檢查用D65 ·營光燈 溫濕度：25°C，成形濕度 照度：3570LX 照射量：120萬Lx · hr 色差測定裝置：彩色分析器TC- 1 800MK-II 測定方法：反射光測定 表色系：CIELAB 測定條件：2度視野 標準光：C 表2 檢體 著色變化（ΛΕ) 色差 匹爾棻尼酮原藥 0.73 少有色差 匹爾棻尼酮壓縮成形品 3.62 有顯著色差 匹爾薬尼酮素銳 5.08 有顯著色差 匹爾棻尼酮錠劑 0.75 少有色差 如表2可知，匹爾棻尼酮原藥在粉末狀_下，目視不認 爲有顏色上變化，但匹爾棻尼酮壓縮成形品及匹爾棻尼酮 素錠則有光安定性上之問題。然而，製成匹爾棻尼酮錠劑 者可解決光安定性之問題。且對於臭味及苦味，匹爾棻尼 酮錠劑亦沒有問題。 -25- 1314868 五、發明說明（24) 產業上可利用性 本發明爲一種可製作將必須多量服用之匹爾棻尼酮爲多 的主藥含量’以壓縮亦具有充·分硬度之錠劑，同時解決臭 味及苦味之問題而易於服用者。且解決錠劑化匹爾棻尼酮 所產生之光安定性的問題，可獲得作爲醫藥品所要求的安 定性。 -26-

Claims (1)

1314868
填請委員明示’本案修正後是否變更原實質….. :、申請專利範圍 第9 1 1 0 1 440號「含有5-甲基-1-苯基-2-(1Η)-吡啶酮爲主 藥之錠劑及其製法」專利案 (93年12月17日修正） 六申請專利範圍： 1. 一種含有5 -甲基-1-苯基- 2- (1Η) -吡啶酮爲主藥之錠 劑，相對於錠劑之全部重量，其含有10〜85重量％之 5-甲基·1_苯基- 2- UH)-吡啶酮，此錠劑含有素錠及 包衣層， 其素錠含有全藥，相對於主藥，以含有選自乳糖、玉 米澱粉、結晶纖維素及甘露糖醇組成之群之10〜50重 量％之賦形劑，選自α化澱粉、羧甲基纖維素鈣、低 取代之羥丙基纖維素、羧甲基澱粉鈉及交聯聚乙烯吡 咯啶酮組成之群之5~40重量％之崩壞劑，及選自羥丙 基纖維素及聚乙烯吡咯酮組成之群之1~10重量％之結 合劑依流動造粒法製得的顆粒，以及 選自硬脂酸鎂及滑石組成之群之〇.5~5重量％之潤滑 劑，及可選擇1〜10重量％之結合劑以打錠方式獲得之 素錠； 以及包衣層含有相對於主藥’含有選自羥丙基甲基纖 維素及羥丙基纖維素組成之群之2〜6重量％之包衣基 劑，選自檸檬酸三乙酯及三乙酸甘油酯組成之群之 0.01〜1重量％之可塑劑，及選自氧化鈦及三氧化二鐵 組成之群之0.0 5-3重量％之遮光劑。 氟 1314868 六、申請專利範圍 2 .如申請專利範圍第1項之錠劑，相對於主藥，素錠含 有1 0〜50重量％之乳糖、5〜40重量％之羧甲基纖維素鈣 、1 ~ 1 0重量％之羥丙基纖維素、及〇 . 5〜5重量％之硬脂 酸鎂’以及相對於主藥，包衣層含有2~6重量％之羥 丙基甲基纖維素、0.01〜1重量％之檸檬酸三乙酯、及 0.05〜3重量％之氧化鈦所構成者。 3.—種含有5-甲基-1-苯基- 2- UH)-吡啶酮作爲主藥之 錠劑，相對於錠劑之全部重量，其含有10〜85重量％ 之5-甲基-卜苯基-2-(1Η)-吡啶酮，此錠劑含有素錠 及包衣層， 其素錠含有主藥，相對於主藥，以含有選自乳糖、玉 米澱粉、及結晶纖維素組成之群之20~30重量％之賦 形劑，及選自羧甲基纖維素鈣、低取代之羥丙基纖維 素、及交聯聚乙烯吡咯啶酮組成之群之7.5〜15重量％ 之崩壞劑，選自羥丙基纖維素及聚乙烯吡咯啶酮組成 之群之2〜5重量％之結合劑依流動造粒法製得的顆粒 ，及 選自硬脂酸鎂及滑石組成之群之0.5〜3重量％之潤滑 劑，及可選擇2〜5重量％之結合劑以打錠方式獲得之 素錠； 以及包衣層含有相對於主藥，含有選自經丙基甲基纖 維素及羥丙基纖維素組成之群之2〜4重量％之包衣基 劑，選自檸檬酸三乙酯及三乙酸甘油酯組成之群之 1314868 六、申請專利範圍 作爲遮光劑。 4 .如申請專利範圍第3項之錠劑，相對於主藥，素錠含 有20〜30重量％之乳糖、7.5~15重量％之羧甲基纖維素 鈣' 2〜5重量％之羥丙基纖維素、及〇.5~3重量％之硬 脂酸鎂，以及相對於主藥，包衣層含有2〜4重量％之 羥丙基甲基纖維素、0.01〜1重量％之檸檬酸三乙酯、 及0.8-3重量％之氧化鈦所構成者。 5 ·如申請專利範圍第1至4項中任一項之錠劑，其中錠 劑的重量爲l〇〇~l〇〇〇mg。 6 ,如申請專利範圍第1至4項中任一項之錠劑，其中主 藥含量爲1 00〜600mg。 7·—種含有5 -甲基-1-苯基- 2- (1Η)_吡啶酮作爲主藥之 錠劑之製造方法，其含下列步驟： A)將相對於錠劑全重量之10〜85重量％之作爲主藥的 5-甲基-1-苯基-2-(1H)-吡啶酮，調製各自相對於 主藥爲10〜50重量％選自乳糖、玉米澱粉、結晶纖 維素及甘露糖醇組成之群的賦形劑及5〜40重量％選 自α化澱粉、羧甲基纖維素鈣、低取代羥基丙基纖 維素、羧甲基澱粉鈉及交聯聚乙烯吡咯啶酮組成之 群的崩壞劑之混合粉末，將1〜1 0重量％選自羥基丙 基纖維素及聚乙烯吡咯啶酮組成之群的結合劑一邊 噴霧一邊以流動層造粒法造粒而得到顆粒之步驟； Β)於所得顆粒，將可選擇5〜40重量％選自α化澱粉、 1314868 六、申請專利範圍 羧甲基纖維素鈣、低取代羥基丙基纖維素、羧甲基 澱粉鈉及交聯聚乙烯吡咯啶酮組成之群的崩壞劑， 及0 . 5〜5重量％選自硬脂酸鎂及滑石組成之群的潤 滑劑加入混合後，以8~ 1 8kN打錠而得到素錠之步 驟； C) 調製含有2~6重量％選自羥基丙基甲基纖維素及羥 基丙基纖維素組成之群的包衣層基劑及〇.〇5〜3重 量％選自氧化鈦及三氧化二鐵組成之群的遮光劑， 並可選擇含有0.01〜1重量％選自檸檬酸三乙酯及三 乙酸甘油酯組成之群的可塑劑之包衣層液之步驟； D) 將所得包衣層液塗覆B)步驟所得素錠而得到錠劑之
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ATE452637T1 (de) 2010-01-15
DE60234812D1 (de) 2010-02-04
WO2002060446A1 (fr) 2002-08-08
EP1356816A1 (en) 2003-10-29
US20160074375A1 (en) 2016-03-17
KR100777169B1 (ko) 2007-11-16
US20120183615A1 (en) 2012-07-19
KR20030072608A (ko) 2003-09-15
JP4077320B2 (ja) 2008-04-16
US20110104276A1 (en) 2011-05-05
US20150209341A1 (en) 2015-07-30
US20040048902A1 (en) 2004-03-11
KR100891887B1 (ko) 2009-04-03
US20170100380A1 (en) 2017-04-13
KR20070093006A (ko) 2007-09-14
US9561217B2 (en) 2017-02-07
US7867516B2 (en) 2011-01-11
EP1356816B1 (en) 2009-12-23
US20130115288A1 (en) 2013-05-09
US9017722B2 (en) 2015-04-28
EP1356816A4 (en) 2005-02-09

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