TWI488627B - 左氧氟沙星或其鹽或該等之溶劑合物之用途 - Google Patents
左氧氟沙星或其鹽或該等之溶劑合物之用途 Download PDFInfo
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- TWI488627B TWI488627B TW099146206A TW99146206A TWI488627B TW I488627 B TWI488627 B TW I488627B TW 099146206 A TW099146206 A TW 099146206A TW 99146206 A TW99146206 A TW 99146206A TW I488627 B TWI488627 B TW I488627B
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- Prior art keywords
- levofloxacin
- eye
- eye drops
- genus
- conjunctivitis
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Classifications
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
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- A—HUMAN NECESSITIES
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Description
本發明為有關含有作為有效成分1.5%(w/v)濃度之左氧氟沙星或其鹽或該等之溶劑合物之眼感染症治療用點眼劑,其為以每眼1滴,每日點眼三次來使用為特徵之點眼劑。
左氧氟沙星(levofloxacin)為藉阻礙DNA促旋酶(DNA gyrase)及拓樸異構酶IV(topoisomerase IV)來表現抗菌活性之新喹啉酮系抗菌劑之一,而被通用。於日本也從左氧氟沙星之廣抗菌範圍和其優異抗菌力,而以左氧氟沙星為有效成分之抗菌點眼藥作為0.5%(w/v)左氧氟沙星點眼液(clubit(註冊商標)點眼液0.5%)來通用。
但即使以0.5%(w/v)左氧氟沙星點眼液也有時無法短期間治癒眼感染症,於如此場合,不得不將左氧氟沙星點眼液長期間繼續使用。另一方面,最近有將0.5%(w/v)左氧氟沙星點眼液長期間使用而出現耐性菌之報告。例如於新眼科,21(11),1531-1534(2004)(非專利文獻1),報告對長期點眼患者之結膜囊實施細菌學的調査結果,相對於左氧氟沙星非點眼組有臨床分離株之24%(6/25)為耐新喹啉酮性,但於0.5%(w/v)左氧氟沙星3個月點眼組,則有臨床分離株之71%(20/28)為耐新喹啉酮性。又於日本眼科學會雜誌,110(12),973-983(2006)(非專利文獻2)亦報告,由細菌性角膜炎患者所臨床分離出之感二甲苯青黴素性金黃色葡萄球菌之約10%為耐左氧氟沙星性。
如此將左氧氟沙星點眼液長期間繼續點眼,則眼感染症產生發炎菌之左氧氟沙星耐性化進展,將來難免有對左氧氟沙星之眼感染症之有效性降低之危險性。更若使左氧氟沙星點眼液之使用期間越長期化,結果越陷於左氧氟沙星耐性化進展之惡性循環。
故以左氧氟沙星點眼液短期間治癒眼感染症,縮短眼感染症產生發炎菌對左氧氟沙星之曝露期間,在阻止左氧氟沙星耐性菌之出現、甚至將來為確保對左氧氟沙星點眼液之眼感染症之有效性上極為重要。但左氧氟沙星點眼液以如何用法或用量來點眼投與,則能以更短期間治癒眼感染症尚未明,又若變更左氧氟沙星點眼液之用法或用量,則比以往之用法或用量(0.5%(w/v),每日點眼三次)反而增大副作用之出現率。故變更左氧氟沙星點眼液之用法或用量時,比以往之用法或用量更短期間治癒眼感染症,則除可阻止左氧氟沙星耐性菌之出現,且可求得比以往之用法或用量不增大副作用之出現率。
但於專利文獻掲示含有0.3~4.0%(w/v)濃度之左氧氟沙星及多元醇之點眼液。但專利文獻1為於左氧氟沙星點眼液摻合多元醇來改善該點眼液之防腐效果之發明,對於將左氧氟沙星點眼液以如何用法或用量點眼投與,則可以更短期間治癒眼感染症,或又可阻止耐性菌之出現則既無記載也無暗示。
故關於左氧氟沙星點眼液,為阻止左氧氟沙星耐性菌之出現,探索比以往之用法或用量以短期間治癒眼感染症,且不增大副作用之出現率之新用法或用量之左氧氟沙星點眼液為頗具意思之課題。
本發明者使用種種用法或用量之左氧氟沙星點眼液施行各種研究結果,發現若選擇每眼將1.5%(w/v)左氧氟沙星點眼液1滴每日點眼三次之用法或用量(以下稱「本用法用量」),則比每眼將0.5%(w/v)左氧氟沙星點眼液1滴每日點眼三次之用法或用量(以下稱「以往用法用量」)之場合,能以短期間治癒細菌性結膜炎,且不增大副作用之出現率,終於完成本發明。因以短期間治癒眼感染症係縮短眼感染症產生發炎菌對左氧氟沙星之曝露期間,故本用法用量之左氧氟沙星點眼液其結果,可期待抑制以往用法用量之左氧氟沙星點眼液長期使用為原因之耐性菌之出現。
又由本發明者使用兔子角膜上皮剝離模型之研究結果,發現以1.5%(w/v)左氧氟沙星點眼液之每日點眼三次於前眼部雖無特異常所見,但將3.0%(w/v)以上濃度之左氧氟沙星點眼液每日點眼三次時,於前眼部發現異常所見及角膜上皮創傷治癒之延遲。本知見暗示,選擇超過1.5%(w/v)濃度(用量)之左氧氟沙星點眼液時,副作用之出現頻度上昇之可能。
本發明者更使用眼球結膜組織濃度模擬之模型繼續研究結果,以往用法用量之左氧氟沙星點眼液以短期間(24小時)之使用導致金黃色葡萄球菌之耐性化,反觀本用法用量之左氧氟沙星點眼液,驚奇地發現此耐性化幾乎完全被阻止。即,本用法用量之左氧氟沙星點眼液可直接抑制因以往用法用量之左氧氟沙星點眼液短期使用之金黃色葡萄球菌等眼感染症產生發炎菌之耐性化。
即,本用法用量之左氧氟沙星點眼液為不增大副作用而以短期間治療眼感染症,有效地抑制以往用法用量之左氧氟沙星之長期及/或短期使用所生眼感染症產生發炎菌耐性化之優異的眼感染症治療用點眼劑。
即,本發明為以含有1.5%(w/v)濃度之左氧氟沙星或其鹽或這些之溶劑合物作為有效成分之眼感染症治療用點眼劑,為以每眼1滴,每日點眼三次來使用為特徵之點眼劑。
又本發明之一態樣為以本用法用量為特徵,且以含有1.5%(w/v)濃度之左氧氟沙星或其鹽或這些之溶劑合物作為有效成分之眼感染症治療用點眼劑,該眼感染症為由結膜炎、眼瞼炎、淚囊炎、麥粒腫及瞼板腺炎而成之群選擇之至少一種感染症之點眼劑。
又本發明之其他態樣為以本用法用量使用為特徵之含有1.5%(w/v)濃度之左氧氟沙星或其鹽或這些之溶劑合物作為有效成分之眼感染症治療用點眼劑,該眼感染症之產生發炎菌為由左氧氟沙星敏感性之葡萄球菌(Staphylococcus)屬、鏈球菌(Streptococcus)屬、肺炎球菌(Streptococcus pneumoniae)、腸球菌(Enterococcus)屬、微球菌(Micrococcus)屬、莫拉氏菌(Moraxella)屬、棒狀桿菌(Corynebacterium)屬、克雷伯氏菌屬(Klebsiella)、腸桿菌屬(Enterobacter)、沙雷氏菌屬(Serratia)、變形桿菌屬(Proteus)、摩氏摩根氏菌(Morganella morganii)、流感嗜血菌(Haemophilus influenzae)、埃及嗜血菌(Haemophilus aegyptius)、假單胞菌(Pseudomonas)屬、綠膿菌(Pseudomonas aeruginosa)、嗜麥芽黃單胞菌(Stenotrophomonas maltophilia)、不動桿菌(Acinetobacter)屬、及瘡疱丙酸桿菌(Propionibacterium acnes)、瘡疱丙酸桿菌而成之群選擇之至少一種菌之點眼劑。
又本發明之其他態樣為以本用法用量使用為特徵,有效成分為含有1.5%(w/v)濃度之左氧氟沙星或其鹽或這些之溶劑合物之結膜炎治療用點眼劑,該結膜炎之產生發炎菌為左氧氟沙星敏感性之葡萄球菌屬之點眼劑。於此結膜炎為細菌性結膜炎、葡萄球菌屬以金黃色葡萄球菌較佳。
由後述臨床試驗之結果明白,本用法用量(1.5%(w/v)每日點眼三次)之左氧氟沙星點眼液為比使用以往用法用量(0.5%(w/v)每日點眼三次)之左氧氟沙星點眼液之情況,由種種產生發炎菌發症之細菌性結膜炎之短期治癒率顯著改善,且雖本用法用量之左氧氟沙星點眼液為比以往用法用量之左氧氟沙星點眼液為高濃度,但副作用之出現率不增大。以短期間治癒眼感染症乃縮短眼感染症產生發炎菌對左氧氟沙星之曝露期間,故本用法用量之左氧氟沙星點眼液以結果而言,可期待抑制因以往用法用量之左氧氟沙星點眼液之長期使用之耐性菌之出現。
又由後述眼毒性試驗之結果也明白,1.5%(w/v)左氧氟沙星點眼液之每日點眼三次雖於前眼部無特別異常所見,但將3.0%(w/v)以上濃度之左氧氟沙星點眼液每日點眼三次時,可認定前眼部之異常所見及角膜上皮創傷治癒之延遲。故選擇超過1.5%(w/v)之濃度(用量)之左氧氟沙星點眼液時,可能使副作用之出現頻率上昇。
更由後述眼內動態試驗及藥理試驗(眼球結膜組織濃度模擬模型)之結果明白,以往用法用量之左氧氟沙星點眼液乃以短期間(24小時)之使用導致金黃色葡萄球菌之耐性化,反觀本用法用量之左氧氟沙星點眼液,則驚奇發現此耐性化幾乎完全被阻止。即,本用法用量之左氧氟沙星點眼液可直接抑制將因以往用法用量之左氧氟沙星點眼液之短期使用之金黃色葡萄球菌等眼感染症產生發炎菌之耐性化。
亦即本用法用量之左氧氟沙星點眼液不增大副作用而以短期間治療眼感染症,因有效抑制由於以往用法用量之左氧氟沙星點眼液之長期及/或短期使用所發生之眼感染症產生發炎菌之耐性化,故可成為優異之眼感染症治療用點眼劑。
此發明之上述及其他目的、特徵、局面及利點可由與所附之圖面關連來理解之有關此發明之如下詳細說明而明白。
左氧氟沙星為呈如下化學構造式(I)之化合物。
左氧氟沙星之鹽只要為醫藥容許鹽則無特限,可為與鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等無機酸之鹽,與乙酸、富馬酸、馬來酸、丁二酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡萄庚酸、葡萄糖醛酸,對酞酸、甲磺酸、乳酸、馬尿酸、1,2-乙二磺酸、羥乙磺酸、乳糖酸、油酸、雙氫萘酸(Pamoic acid)、聚半乳糖醛酸、硬脂酸、單寧酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺基柳酸等有機酸之鹽,與甲基溴、甲基碘等之四級銨鹽,與溴離子、氯離子、碘離子等鹵素離子之鹽,與鋰、鈉、鉀等鹼金屬之鹽,與鈣、鎂等鹼土類金屬之鹽,與鐵、鋅等之金屬鹽,與氨之鹽、三乙二胺、2-胺基乙醇、2,2-亞胺基雙(乙醇)、1-去氧-1-(甲胺基)-2-D-山梨糖醇、2-胺基-2-(羥甲基)-1,3-丙二醇、普魯卡因、N,N-雙(苯甲基)-1,2-乙二胺等有機胺之鹽等。
左氧氟沙星或其鹽之溶劑合物只要為醫藥容許之溶劑合物則無特限,可為水合物(1/2水合物、1水合物、2水合物等)、有機溶劑合物等,惟宜為水合物(1/2水合物、1水合物或2水合物)。
於左氧氟沙星或其鹽或這些之溶劑合物有結晶多形及結晶多形群(結晶多形系)存在時,這些結晶多形體及結晶多形群(結晶多形系)也包括於本發明之範圍。於此,結晶多形群(結晶多形系)乃指依這些結晶之製造、晶體形成、保存等之條件及狀態(於本狀態也包括製劑化之狀態),於結晶形變化時之各段階各結晶形及其過程全體。
本發明之左氧氟沙星或其鹽或這些之溶劑合物較佳為左氧氟沙星之水合物,更較佳為左氧氟沙星之1/2水合物。
左氧氟沙星或其鹽或這些之溶劑合物可依特公平3-27534號公報及特公平7-47592號公報記載之方法製造。又本發明中,也可用市售之左氧氟沙星鹽酸鹽(和光純藥公司製、型錄號碼:555-70931等)。
本發明中,1.5%(w/v)左氧氟沙星點眼液(以下稱「本點眼液」)為含有1.5%(w/v)濃度之左氧氟沙星(游離體)或其鹽或這些之溶劑合物作為有效成分之點眼液。
本點眼液可使用習用技術,必要時使用製藥學上容許之添加劑來調製。
本點眼液必要時可將由例如氯化鈉、濃甘油等之等張化劑;鹽酸、氫氧化鈉等pH調整劑;磷酸鈉、乙酸鈉等緩衝化劑;聚氧乙烯山梨糖醇單油酸酯、聚氧乙烯40硬脂酸酯、聚氧乙烯硬化蓖麻油等界面活性劑;檸檬酸鈉、乙二胺四乙酸鈉等安定化劑;氯化烷基二甲基苄基銨、對羥基苯甲酸酯等防腐劑等選擇使用來調製。本點眼液之pH只要為眼科製劑容許範圍內即可,但通常以4~8之範圍內較佳。
本發明中,將本點眼液「1滴」點眼,通常乃指將10~60μL本點眼液點眼。
本發明中,本點眼液之「每日點眼三次」乃指24小時以內將本點眼液點眼三次,宜為於晨、晝及夜各點眼一次。
本發明中,眼感染症(ocular infection)可為結膜炎(conjunctivitis)、角膜炎(keratitis)、眼瞼炎(blepharitis)、淚囊炎(dacryoadenitis)、淚小管炎(lacrimal canaliculitis)、瞼板腺炎(inflammation of the tarsal gland)、麥粒腫(hordeolum)及眼內炎(endophthalmitis)等。
本發明中,結膜炎之具體例可為細菌性結膜炎(bacterial conjunctivitis)、炎症性結膜炎(catarrhal conjunctivitis)、化膿性結膜炎(purulent conjunctivitis)、偽膜性結膜炎(pseudomembranous conjunctivitis)、結膜泡性炎(conjunctival phlyctenule)等;角膜炎之具體例可為細菌性角膜炎(bacterial keratitis)、角膜潰瘍(corneal ulcer)、角膜泡性炎(corneal phlyctenule)等;眼瞼炎之具體例可為眼瞼緣炎(marginal blepharitis)、眼瞼皮膚炎(eyelid dermatitis)、眼角眼瞼炎(angular blepharitis)、葡萄球菌性眼瞼炎(staphylococcal blepharitis)、脂漏性眼瞼炎(seborrheic blepharitis)等;淚囊炎之具體例可為急性淚囊炎(acute dacryocystitis)、慢性淚囊炎(chronic dacryocystitis)、新生兒淚囊炎(dacryocystitis of the newborn)等;麥粒腫之具體例可為外麥粒腫(external hordeolum)、內麥粒腫(internal hordeolum)等;眼內炎之具體例可為細菌性眼內炎(bacterial endophthalmitis)、內眼手術後之術後眼內炎(endophthalmitis after intraocular surgery)等。
本發明中,於細菌性結膜炎包括急性細菌性結膜炎(acute bacterial conjunctivitis)及慢性細菌性結膜炎(chronic bacterial conjunctivitis),於瞼板腺炎包括瞼板腺炎(meibomitis)。又於本發明中內眼手術包括白內障手術、綠內障手術、網膜玻璃體手術等。
使用本用法用量之左氧氟沙星點眼液之眼感染症之較佳為由結膜炎、眼瞼炎、淚囊炎、麥粒腫及瞼板腺炎而成之群選擇之至少一種感染症,更較佳為結膜炎,再更佳為細菌性結膜炎。
作為本發明之眼感染症之產生發炎菌可為例如左氧氟沙星敏感性之葡萄球菌屬(genus Staphylococcus)、鏈球菌屬(genus Streptococcus)、肺炎球菌(Streptococcus pneumoniae)、腸球菌屬(genus Enterococcus)、微球菌屬(genus Micrococcus)、莫拉氏菌屬(genus Moraxella)、棒狀桿菌屬(genus Corynebacterium)、克雷伯氏菌屬(genus Klebsiella)、腸桿菌屬(genus Enterobacter)、沙雷氏菌屬(genus Serratia)、變形桿菌屬(genus Proteus)、摩氏摩根氏菌(Morganella morganii)、流感嗜血菌(Haemophilus influenzae)、埃及嗜血菌(Haemophilus aegyptius)、假單胞菌屬(genus Pseudomonas)、綠膿菌(Pseudomonas aeruginosa)、嗜麥芽黃單胞菌(Stenotrophomonas maltophilia)、不動桿菌屬(genus Acinetobacter)、瘡疱丙酸桿菌(Propionibacterium acnes)、淋病雙球菌(Neisseria gonorrhoeae)、芽胞桿菌屬(genus Bacillus)、梭菌屬(genus Clostridium)、叢毛單胞菌屬(genus Comamonas)等。
本發明中,前述葡萄球菌屬之具體例可為金黃色葡萄球菌(Staphylococcus aureus)、凝固酶陰性葡萄球菌(Coagulase Negative Staphylococcus)等;前述鏈球菌屬之具體例可為α型鏈球菌(α-hemolytic Streptococcus)、β型鏈球菌(β-hemolytic Streptococcus)、γ型連鎖球菌(γ-hemolytic Streptococcus)、A群鏈球菌(Group A Streptococcus)、B群鏈球菌(Group B Streptococcus)、C群鏈球菌(Group C Streptococcus)、D群鏈球菌(Group D Streptococcus)、E群鏈球菌(Group E Streptococcus)、F群鏈球菌(Group F Streptococcus)、G群鏈球菌(Group G Streptococcus)、H群鏈球菌(Group H Streptococcus)、K群鏈球菌(Group K Streptococcus)、L群鏈球菌(Group L Streptococcus)、M群鏈球菌(Group M Streptococcus)、N群鏈球菌(Group N Streptococcus)、O群鏈球菌(Group O Streptococcus)、P群鏈球菌(Group P Streptococcus)、Q群鏈球菌(Group Q Streptococcus)、R群鏈球菌(Group R Streptococcus)、S群鏈球菌(Group S Streptococcus)、T群鏈球菌(Group T Streptococcus);腸球菌屬之具體例可為糞腸球菌(Enterococcus faecalis)、耐久腸球菌(Enterococcus durans)等;前述微球菌屬之具體例可為Micrococcus lylae等;前述莫拉氏菌屬之具體例可為卡他莫拉氏菌(Moraxella Branhamella catarrhalis)、Moraxella-Axenfeld bacillus(包括腔隙莫拉氏菌(Moraxella lacunata)、液化莫拉氏菌(Moraxella liquefaciens)及牛莫拉氏菌(Moraxella bovis)等;前述棒狀桿菌屬之具體例可為Corynebacterium species(包括白喉棒狀桿菌(Corynebacterium nebacterium diphtheriae)、假白喉棒狀桿菌(Corynebacterium pseudodiphthericum)及乾燥棒狀桿菌Corynebacterium xerosis)等;前述克雷伯氏菌屬之具體例可為產酸克雷伯氏菌(Klebsiella oxytoca)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、土生克雷伯菌(Klebsiella terrigena)、植生克雷伯菌(Klebsiella planticola)等;前述腸桿菌屬之具體例可為產氣腸桿菌(Enterobacter aerogenes)、集聚腸桿菌(Enterobacter agglomerans)、陰溝腸桿菌(Enterobacter cloacae)等;前述沙雷氏菌屬之具體例可為黏質沙雷氏菌(Serratia marcescens)等;前述變形桿菌屬之具體例可為奇異變形桿菌(Proteus mirabilis)、普通變形桿菌(Proteus vulgaris)等;前述假單胞菌屬之具體例可為產鹼假單胞菌(Pseudomonas alcaligenes)、泡囊假單胞菌(Pseudomonas vesicularis)、洋葱假單胞菌(Pseudomonas cepacia)、綠針假單胞菌(Pseudomonas chlororaphis)、螢光假單胞菌(Pseudomonas fluorescens)、帕氏假單胞菌(Pseudomonas pickettii)、惡臭假單胞菌(Pseudomonas putida)等;前述不動桿菌屬之具體例可為乙酸鈣不動桿菌(Acinetobacter calcoaceticus)、包曼氏不動桿菌(Acinetobacter baumannii)、魯氏不動桿菌(Acinetobacter lwoffii)等;前述芽胞桿菌屬之具體例可為蠟狀芽胞桿菌等(bacillus cereus);前述梭菌屬之具體例可為產氣梭菌(Clostridium perfringens)、破傷風梭菌(Clostridium tetani)等;前述叢毛單胞菌屬之具體例可為食酸叢毛單胞菌(Comamonas acidovorans)等。
本發明中,前述金黃色葡萄球菌包括感二甲苯青黴素性金黃色葡萄球菌(MSSA)及耐二甲苯青黴素性金黃色葡萄球菌(MRSA)、前述表皮葡萄球菌包括感二甲苯青黴素性表皮葡萄球菌(MSSE)及耐二甲苯青黴素性表皮葡萄球菌(MRSE)。又本發明中,前述凝固酶陰性葡萄球菌包括頭葡萄球菌(S.capitis)、山羊葡萄球菌(S.caprae)、溶血性葡萄球菌(S.haemolyticus)、人葡萄球菌(S.hominis)、里昂葡萄球菌(S.lugdunensis)、松鼠葡萄球菌(S.sciuri)、擬葡萄球菌(S.simulans)及瓦氏葡萄球菌(S.warneri)、鏈球菌屬包括無乳鏈球菌(Streptococcus agalactiae)、似馬鏈球菌(Streptococcus equisimilis)、草綠色鏈球菌(Streptococcus gordonii)、緩症鏈球菌(Streptococcus mitis)、麻疹鏈球菌(Streptococcus morbillorum)、口腔鏈球菌(Streptococcus oralis)及釀膿鏈球菌(Streptococcus pyogenes)。
本發明中,「左氧氟沙星敏感性」乃指其菌株於臨床上通常使用濃度之左氧氟沙星中被充分殺菌或抑菌。
使用本用法用量之左氧氟沙星點眼液之眼感染症較佳為以由左氧氟沙星敏感性之葡萄球菌屬、鏈球菌屬、肺炎球菌、腸球菌屬、微球菌屬、莫拉氏菌屬、棒狀桿菌屬、克雷伯氏菌屬、腸桿菌屬、沙雷氏菌屬、變形桿菌屬、摩氏摩根氏菌、流感嗜血菌、埃及嗜血菌、假單胞菌屬、綠膿菌、嗜麥芽黃單胞菌、不動桿菌屬及瘡疱丙酸桿菌而成之群選擇之至少一種菌為產生發炎菌之眼感染症,更較佳為以左氧氟沙星敏感性之葡萄球菌屬為產生發炎菌之眼感染症,再更佳為以左氧氟沙星敏感性之金黃色葡萄球菌為產生發炎菌之眼感染症,最佳為以左氧氟沙星敏感性之MSSA為產生發炎菌之眼感染症。
本發明中,於眼感染症治療用點眼劑對前述眼感染症不只包括用於治療,也包括用於感染預防之點眼劑。又本發明中眼感染症之感染預防包括眼科手術期之無菌化療法。
以下列示臨床試驗、眼毒性試驗、眼內動態試驗及藥理試驗之結果,及製劑例,但這些例為用以使本發明更充分理解者,非限定本發明之範圍。
實施如下示臨床試驗,將本用法用量之1.5%(w/v)左氧氟沙星點眼液之每日點眼三次群,與以往用法用量之0.5%(w/v)左氧氟沙星點眼液之每日點眼三次群,比較研究對細菌性結膜炎之影響(有效性及安全性)。
1.5%(w/v)左氧氟沙星點眼液及0.5%(w/v)左氧氟沙星點眼液為將左氧氟沙星1/2水合物溶解於水,添加等張化劑(甘油)及pH調節劑,而依習用技術來調製(pH:6.1~6.9)。
對細菌性結膜炎患者將1.5%(w/v)左氧氟沙星點眼液或0.5%(w/v)左氧氟沙星點眼液以一次1滴,每日三次之用法用量最大點眼14日。以點眼開始日、點眼第3、7及14日為基準日,調査患者之眼脂(眼分泌)及充血之程度,及其他自覺症狀及他覺所見,並實施細菌檢査來評價細菌(推定產生發炎菌)之消失日數,而研究本用法用量之左氧氟沙星點眼液之有效性及安全性。
就眼脂(眼分泌)及充血,依如下表1評分施行調査。又就浮腫、眼瞼腫脹、眼痛、畏光、流淚等其他自覺症狀及他覺所見,以未認出症狀或所見之場合為0點,以症狀或所見最重之場合為3點,依評分施行調査(依症狀或所見之重度定為0點、0.5點、1點、2點、3點)。
由感染部位採取檢體,依習用之方法實施細菌之分離鑑定及感受性試驗。
至以點眼第3日為基準日之觀察日(第二次觀察日)於點眼開始日(初次觀察日)檢測出之菌(推定產生發炎菌)消失,且於以點眼第7日為基準之觀察日(第三次觀察日)眼脂(眼分泌)及充血之中,主治醫師判斷為主症狀者消失之情況(評分為0點之場合)判斷為「短期治癒」。但第三次觀察日中依包括眼脂(眼分泌),充血之評分施行調査之自覺症狀及他覺所見(以下將這些簡單統稱「自他覺症狀」)之合計評分超過點眼開始日之自他覺症狀之合計評分之1/4之場合不當作「短期治癒」。
於左氧氟沙星點眼液投與後觀察之全部自覺症狀之出現或惡化,及主治醫師於醫學上判斷為有害之全部他覺所見之出現或惡化之中,以不能明確否定與左氧氟沙星點眼液之因果關係者作為副作用。又即使以於早期由試驗脫落等理由而不成為有效性評價之對象之情況,也將1.5%(w/v)左氧氟沙星點眼液或0.5%(w/v)左氧氟沙星點眼液即使一次點眼之被驗者作為安全性評價之對象。
如表2所示,本用法用量之點眼組[1.5%(w/v)左氧氟沙星點眼液每日三次],與以往用法用量之點眼組[0.5%(w/v)左氧氟沙星點眼液每日三次]比較,認定顯著改善對細菌性結膜炎之短期治癒率,對由供試驗之產生發炎菌發症之全部細菌性結膜炎,為75%以上之高短期治癒率。尤其以MSSA或MRSA為產生發炎菌時,本用法用量對細菌性結膜炎之短期治癒率各為97.1%或100%,比以往用法用量之短期治癒率(56.5%或33.3%)大幅地改善。
接著如表3所示,本用法用量之點眼組與以往用法用量之點眼組,於副作用出現率未認出實質之差。值得注意的是,本用法用量之左氧氟沙星點眼液之濃度(1.5%(w/v)),比以往用法用量之濃度(0.5%(w/v))雖為高濃度,但副作用之出現率為相同程度。
由臨床試驗之結果,暗示本用法用量之左氧氟沙星點眼液,比以往用法用量之左氧氟沙星點眼液,能以短期間治癒細菌性結膜炎所代表之眼感染症,且副作用之出現率也與以往用法用量之情況相同程度。
又以短期間治癒眼感染症乃縮短眼感染症產生發炎菌與左氧氟沙星之曝露期間,故本用法用量之左氧氟沙星點眼液以結果而言,可期待抑制因以往用法用量之左氧氟沙星點眼液之長期使用之耐性菌之出現。
使用兔子角膜上皮剝離模型,研究本用法用量之左氧氟沙星點眼液及超過本用法用量之用法用量之左氧氟沙星點眼液,是否導致角膜上皮創傷治癒之延遲及其他前眼部之異常。
將左氧氟沙星1/2水合物溶解於水,添加等張化劑(甘油)及pH調節劑,而調製1.5%(w/v)、3.0%(w/v)及6.0%(w/v)之左氧氟沙星點眼液(pH:6.1~6.9),以不含左氧氟沙星之點眼液為基劑而用於本試驗。
使用雄性兔子,依照Cintron等人之方法(Ophthalmic Res.,11,90-96(1979)),製作兔子角膜上皮剝離模型。
將基劑或1.5%(w/v)、3.0%(w/v)或6.0%(w/v)之左氧氟沙星點眼液,於各角膜剝離處理當日三次、角膜剝離處理次日也三次,於上述兔子點眼(即,將每日點眼三次重複實施2日)。一次之點眼量為每眼50μL。
於角膜剝離即後實施角膜上皮創傷部位之照像攝影,將兔子分為基劑組及1.5%(w/v)、3.0%(w/v)及6.0%(w/v)左氧氟沙星點眼組(各組4例8眼)、施行如上述點眼。於剝離24及48小時後,再度實施角膜上皮創傷部位之照像攝影。又將前眼部觀察(角膜混濁、充血等)於角膜剝離處理前和剝離24及48小時後之照像攝影開始前施行。各組剝離24及48小時後之前眼部症狀如表4所示。又角膜上皮創傷面積率以剝離即後之角膜上皮創傷面積為100%,依下式於各觀察時間(剝離24及48小時後)算出。
角膜上皮創傷面積率(%)=(各觀察時間之創傷面積/剝離即後之創傷面積)×100
各組之剝離24及48小時後之前眼部症狀如表4所示。又表之括弧內乃示(有所見之眼數/全眼數)。如表4所示,即使將1.5%(w/v)左氧氟沙星點眼液每日點眼三次,於角膜剝離兔子之前眼部症狀也未認出異常所見。另一方面,將3.0%(w/v)左氧氟沙星點眼液每日點眼三次時,於角膜剝離48小時後,於全例認出充血(8眼中8眼)。更於將6.0%(w/v)左氧氟沙星點眼液每日點眼三次,於角膜剝離24小時後,認出充血(8眼中7眼)、眼瞼腫脹(8眼中4眼)及眼脂(8眼中2眼)、剝離48小時後,認出充血(8眼中8眼)及角膜混濁(8眼中5眼)。
又由表示各組之角膜上皮損傷面積率之表5明白,於1.5%(w/v)及3.0%(w/v)左氧氟沙星點眼液之每日點眼三次、角膜剝離24及48小時後,皆未認出角膜上皮創傷面積率之上昇。另一方面,於6.0%(w/v)左氧氟沙星點眼液之每日點眼三次,確認角膜上皮創傷面積率之顯著上昇。
由以上暗示將1.5%(w/v)左氧氟沙星點眼液每日點眼三次時,未認出前眼部之異常所見及角膜上皮創傷治癒之延遲,另一方面,於將3.0%(w/v)以上濃度之左氧氟沙星點眼液每日點眼三次時,於前眼部認出異常所見,而6.0%(w/v)濃度之左氧氟沙星點眼液每日點眼三次係使其延遲角膜上皮創傷治癒。故選擇超過1.5%(w/v)濃度(用量)之左氧氟沙星點眼液時,暗示副作用之出現頻度上昇之可能性。
為評價1.5%(w/v)左氧氟沙星點眼液及0.5%(w/v)左氧氟沙星點眼液之點眼後之眼內動態,使用兔子實施將各濃度之左氧氟沙星點眼液點眼一次時之眼內動態試驗。
將左氧氟沙星1/2水合物溶解於水,添加等張化劑(甘油)及pH調節劑,而依習用技術調製(pH:6.1~6.9)。
使用市售之clubit(註冊商標)
點眼液0.5%(參天製藥公司製)。
於兔子(雄性日本白色種,各組5或6例)之右眼將1.5%(w/v)左氧氟沙星點眼液,於左眼將0.5%(w/v)左氧氟沙星點眼液各50μL點眼一次。於點眼0.25、0.5、1、2、4、6及8小時後,犧牲兔子而摘出眼球結膜,將眼球結膜中之左氧氟沙星濃度使用高速液體層析來測定。
表6及第1圖乃示將1.5%(w/v)左氧氟沙星點眼液或0.5%(w/v)左氧氟沙星點眼液各點眼一次後,眼球結膜中之左氧氟沙星濃度之變遷。由這些試驗結果,1.5%(w/v)左氧氟沙星點眼液及0.5%(w/v)左氧氟沙星點眼液,皆可確認投與8小時後之眼球結膜中濃度比各自之投與後初期時間之眼球結膜中濃度變得充分地低,故可認為即使將這些點眼液以8小時間隔每日三次投與,也殆無眼球結膜中左氧氟沙星濃度之積昇。
就本用法用量之1.5%(w/v)左氧氟沙星點眼液之每日點眼三次,與以往用法用量之0.5%(w/v)左氧氟沙星點眼液之每日點眼三次,是否於點眼後出現耐性菌,使用眼球結膜組織中濃度模擬模型來比較研究。
由外眼部感染症患者分離MSSA(對左氧氟沙星之MIC=0.5μg/mL)。
由前述眼內動態試驗所得左氧氟沙星點眼後之眼球結膜動態(表6及第1圖),推定1.5%(w/v)左氧氟沙星點眼液,及0.5%(w/v)左氧氟沙星點眼液每日點眼三次後之左氧氟沙星之24小時內之眼球結膜動態。將其濃度變遷再現於活體外培養系統(將眼球結膜中濃度ng/g組織換算為μg/mL),使左氧氟沙星於MSSA作用24小時。具體而言,於含有表7所示濃度之左氧氟沙星的Mueller Hinton broth以表中所示之時間,將MSSA封入之洋菜塊(約0.5~1×108
CFU/mL)浸漬,依表所示之順序,將洋菜塊逐歩移入於含有左氧氟沙星之Mueller Hinton broth。
將此操作重複三次後(以左氧氟沙星處理合計24小時後),由洋菜塊回收菌株,以生理食鹽液製作101
倍~106
倍之10倍稀釋系列。將各菌液之原液及各稀釋菌液50μL滴下於含有0.5、1、2、4及8μg/mL之左氧氟沙星之Mueller Hinton agar、或不含左氧氟沙星之Mueller Hinton agar,靜置約15分鐘後,予以Conradi塗抹,於35℃施行嗜氣培養2日(各組3例)。培養後,計測發育之菌叢數,而算出每1mL之活菌數,來施行種群分析。又在未以左氧氟沙星前處理之菌液也施行同樣之操作。
由第2圖明白,至於以1.5%(w/v)左氧氟沙星點眼液每日點眼三次時(本用法用量)之與結膜組織中濃度相當濃度之左氧氟沙星前處理之MSSA,則與未以左氧氟沙星前處理之情形同樣,即使於含有0.5μg/mL左氧氟沙星之培養基也不形成菌叢,未認出左氧氟沙星之耐性化。反觀以0.5%(w/v)左氧氟沙星點眼液每日點眼三次時(以往用法用量)之與結膜組織中濃度相當濃度之左氧氟沙星前處理之MSSA,即使於含有8μg/mL左氧氟沙星之培養基也形成菌叢,確認高度發生左氧氟沙星之耐性化。
由藥理試驗(眼球結膜組織中濃度模擬模型)之結果,暗示以往用法用量之左氧氟沙星點眼液乃於點眼後24小時導致MSSA之左氧氟沙星耐性化,反觀本用法用量之左氧氟沙星點眼液,則此耐性化幾乎完全被阻止。即,本用法用量之左氧氟沙星點眼液直接抑制在以往用法用量之左氧氟沙星點眼液之短期使用發生耐性化之眼感染症產生發炎菌,尤其以MSSA(金黃色葡萄球菌)代表之葡萄球菌屬之耐性化。
故由前述臨床試驗及本藥理試驗(眼球結膜組織濃度模擬模型)綜合所得知見,則本用法用量之左氧氟沙星點眼液不增大副作用而以短期間治療眼感染症,且有效抑制以往用法用量之左氧氟沙星點眼液之長期及/或短期使用所發生之眼感染症產生發炎菌之耐性化,可成為優異之眼感染症治療用點眼劑。
舉製劑例更具體地說明本發明之藥劑,但本發明不受這些製劑例限定。
處方例1:點眼劑(1.5%(w/v))
100ml中
左氧氟沙星1/2水合物 1500mg
氯化鈉 900mg
滅菌純水 適量
於滅菌純水添加左氧氟沙星1/2水合物及其以外之上述成分,將這些充分混合則可調製上述點眼劑。
處方例2:點眼劑(1.5%(w/v))
100ml中
左氧氟沙星(游離體) 1500mg
濃甘油 2600mg
滅菌純水 適量
於滅菌純水添加左氧氟沙星(游離體)及其以外之上述成分,將這些充分混合則可調製上述點眼劑。
雖將此發明詳細說明,但此僅為例示,非為限定,發明之範圍乃由所附之申請專利範圍解釋可明白理解。
本用法用量之左氧氟沙星點眼液為以比以往用法用量之左氧氟沙星點眼液以更短期間治癒眼感染症,並以副作用之出現率也不增大為特徵。因以短期間治癒眼感染症乃縮短眼感染症產生發炎菌與左氧氟沙星之曝露期間,故本用法用量之左氧氟沙星點眼液以結果而言,可期待抑制以長期使用以往用法用量之左氧氟沙星點眼液為原因之耐性菌之出現。又本用法用量之左氧氟沙星點眼液可將因以往用法用量之左氧氟沙星點眼液之短期使用之金黃色葡萄球菌等眼感染症產生發炎菌之耐性化直接抑制。即,本用法用量之左氧氟沙星點眼液不增大副作用而以短期間治療眼感染症,且為有效抑制由於以往用法用量之左氧氟沙星點眼液之長期及/或短期使用所生之眼感染症產生發炎菌之耐性化之優異的眼感染症治療用點眼劑。
第1圖為表示將1.5%(w/v)左氧氟沙星點眼液或0.5%(w/v)左氧氟沙星點眼液各點眼一次後之眼球結膜中之左氧氟沙星濃度之變遷之圖,縱軸為眼球結膜中左氧氟沙星濃度(ng/g組織),横軸為投與後時間(hr)。
第2圖為表示就1.5%(w/v)左氧氟沙星前處理,0.5%(w/v)左氧氟沙星前處理,無左氧氟沙星前處理之各組之左氧氟沙星濃度與活菌數之關係之圖,縱軸為活菌數(logCFU/mL),横軸為左氧氟沙星濃度(μg/mL)。
Claims (4)
- 一種左氧氟沙星(levofloxacin)或其鹽或這些之溶劑合物之用途,其係用於製造含有1.5%(w/v)濃度之左氧氟沙星或其鹽或這些之溶劑合物作為有效成分之結膜炎治療用點眼劑,該點眼劑係以每眼1滴,每日點眼三次使用。
- 如申請專利範圍第1項之用途,其中結膜炎之產生發炎菌為由左氧氟沙星敏感性之葡萄球菌(Staphylococcus)屬、鏈球菌(Streptococcus)屬、肺炎球菌(Streptococcus pneumoniae)、腸球菌(Enterococcus)屬、微球菌(Micrococcus)屬、莫拉氏菌(Moraxella)屬、棒狀桿菌(Corynebacterium)屬、克雷伯氏菌屬(Klebsiella)、腸桿菌屬(Enterobacter)、沙雷氏菌屬(Serratia)、變形桿菌屬(Proteus)、摩氏摩根氏菌(Morganella morganii)、流感嗜血菌(Haemophilus influenzae)、埃及嗜血菌(Haemophilus aegyptius)、假單胞菌(Pseudomonas)屬、綠膿菌(Pseudomonas aeruginosa)、嗜麥芽黃單胞菌(Stenotrophomonas maltophilia)、不動桿菌(Acinetobacter)屬、及瘡疱丙酸桿菌(Propionibacterium acnes)而成之群選擇之至少一種菌。
- 如申請專利範圍第2項之用途,其中結膜炎之產生發炎菌為左氧氟沙星敏感性之葡萄球菌屬。
- 如申請專利範圍第3項之用途,其中結膜炎為細菌性結膜炎,而葡萄球菌屬為金黃色葡萄球菌。
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