TWI556838B - 治療關節炎之方法 - Google Patents
治療關節炎之方法 Download PDFInfo
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- TWI556838B TWI556838B TW102124244A TW102124244A TWI556838B TW I556838 B TWI556838 B TW I556838B TW 102124244 A TW102124244 A TW 102124244A TW 102124244 A TW102124244 A TW 102124244A TW I556838 B TWI556838 B TW I556838B
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- Prior art keywords
- arthritis
- sustained release
- phospholipid
- release composition
- cholesterol
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Description
本申請案主張2012年7月5日申請之美國申請案第61/668,446號及2013年3月15日申請之美國申請案第61/791,650號的權益,該等申請案之全部揭示內容係以引用的方式併入本文中。
本發明係關於一種治療關節炎之方法,且特別是有關於一種包含投與包含以下各物之組合的持續釋放組合物:(a)包含磷脂或磷脂混合物及膽固醇之脂質體;及(b)治療劑之治療關節炎之方法。
骨關節炎(OA)為最常見類型之關節炎且為造成失能之主要原因。其為一種非發炎性的退化性關節病,特徵為關節軟骨漸進性損失、軟骨下部之骨硬化、形成骨贅、滑膜變化及滑液體積增加,伴隨黏度降低,由此潤滑特性改變。
類風濕性關節炎(RA)為一種病因不明的慢性全身性發炎疾病。遺傳、環境、賀爾蒙、免疫及感染因素均可起到重要作用。此病狀之標誌特徵為影響手及足之持久對稱之多發性關節炎,不過任何由滑膜內襯之關節均會涉及。
此歸因於滑膜襯裡中發炎細胞之累積及增殖,稱為滑膜炎。非關節之器官,諸如皮膚、心臟、肺及眼睛,也會被顯著影響。
關節內(IA)藥物注射為一種有吸引力之關節炎,包括OA及RA,之治療方法。市場銷售之各種類固醇及玻尿酸調配物為有效的,但均需要頻繁的IA注射且僅提供短期的症狀緩解。其他需要大孔針進行IA注射之晶體懸浮液調配物不適於治療小的關節且可產生晶體誘發之滑膜炎。可用之全身性治療亦具有缺點,最顯著地為副作用。
考慮到以上概述之不足,需要一種用於治療關節炎之方法,其IA注射不太頻繁及/或較長時期地緩解疼痛。本文揭示之方法滿足此需要以及其他重要需要。
本文所用之術語「本發明(invention、the invention、this invention及the present invention)」意欲泛指本專利申請案及以下申請專利範圍之所有主題。應瞭解含有此等術語之陳述不限制本文所述之主題或不限制以下專利申請專利範圍之含義或範疇。本發明內容為本發明之各種態樣之高階概述,且引入一些將在以下實施方式部分進一步描述之概念。本發明內容既不欲確認所主張之主題之關鍵或基本特徵,亦不欲獨立用於確定所主張之主題之範疇。主題應藉由參考整個說明書之適當部分、任何或所有圖式及每一申請專利範圍來瞭解。
本發明係有關治療關節炎之方法,其包含向需要該治療之個體經關節內注射持續釋放組合物,藉此減輕個體
中之關節炎症狀。本發明特別有效用於治療類風濕性關節炎。
本發明之持續釋放組合物包含以下各物之組合:(a)包含磷脂或磷脂混合物及膽固醇之脂質體;及(b)治療劑或其醫藥學上可接受之鹽,其中該等脂質體處於水性懸浮液中。
該持續釋放組合物可藉由將脂質混合物與治療劑混合來製備。
圖1為展示4組大鼠分別經受生理食鹽水、游離***磷酸鈉(DSP)或持續釋放組合物之單次IA注射後之體重變化的線圖。
圖2為展示4組大鼠分別經受生理食鹽水、游離DSP或持續釋放組合物之單次IA注射後之臨床目測關節炎評分變化的線圖。
圖3為展示4組大鼠分別經受生理食鹽水、游離DSP或持續釋放組合物之單次IA注射後之右足踝體積變化的線圖。
圖4為展示4組大鼠分別經受生理食鹽水、游離DSP或持續釋放組合物之單次IA注射後之左足踝體積變化的線圖。
圖5為展示3組大鼠在游離DSP或持續釋放組合物之持續四次之每日一次IA注射後的體重變化的線圖。
圖6為展示3組大鼠在各組分別經受游離DSP或持續釋放組合物之持續四次之每日一次IA注射後的臨床目測關節炎評分變化的線圖。
圖7為展示3組大鼠在各組分別經受游離DSP或持續釋
放組合物之持續四次之每日一次IA注射後的右足踝體積變化的線圖。
圖8為展示3組大鼠在各組分別經受游離DSP或持續釋放組合物之持續四次之每日一次IA注射後的左足踝體積變化的線圖。
圖9為展示3組大鼠在游離吲哚美辛(indomethacin)或吲哚美辛持續釋放組合物之持續五次之每日一次注射後的重量變化(圖a)及臨床關節炎評分變化(圖b)的線圖。第19天之第一個箭頭指示第一次每日一次之吲哚美辛投與,且第23天之第二個箭頭指示最後一次每日一次之吲哚美辛投與。
圖10為展示3組大鼠在游離依那西普(etanercept)或依那西普持續釋放組合物之兩次注射後之重量變化(圖a)及臨床關節炎評分變化(圖b)的線圖。第23天之第一個箭頭指示第一次依那西普投與,且第26天之第二個箭頭指示第二次依那西普投與。
圖11為展示3組大鼠在游離甲胺喋呤(methotrexate)或甲胺喋呤持續釋放組合物之兩次注射後之重量變化(圖a)及臨床關節炎評分變化(圖b)的線圖。第23天之第一個箭頭指示第一次甲胺喋呤投與,且第26天之第二個箭頭指示第二次甲胺喋呤投與。
如本文所揭示,向個體IA投與有效量之本文描述之持續釋放組合物可有利地減輕個體之關節炎的徵象及/或症狀。亦發現本文揭示之關節炎治療所需要的IA注射次數可能不如先前已知之治療頻繁。亦發現本文揭示之關節炎治療
比先前已知之治療更長時期地緩解疼痛。此等發現在本文描述之用於治療關節炎之方法、組合物及藥劑中以及用於治療關節炎之組合物的用途中有所體現。
定義
除非另外指示,否則應瞭解如上文所採用且在本發明中,以下術語具有以下含義。
除非上下文另外清楚地指示,否則如本文所用,單數形式「一(a/an)」及「該」包括複數個提及物。
如本文所用之術語「脂質體(liposome/liposomes)」及相關術語包括多囊泡脂質體(MVL)、多層囊泡(MLV)或者小或大的單層囊泡(ULV)。脂質體為奈米尺寸且包含形成粒子之組分及載運藥劑之組分。形成粒子之組分形成一個封閉的脂質障壁,實質上不含諸如三酸甘油酯之中性脂質。在一個實施例中,形成粒子之組分中存在不足約0.1%之中性脂質。在另一個實施例中,形成粒子之組分中無中性脂質。載運藥劑之組分包含實質上水性介質,實質上不含諸如三酸甘油酯之中性脂質、非水性相(油相)、水-油乳液或含有非水性相之其他混合物。
如本文所用之術語「有效量」係指持續釋放組合物足以減輕關節炎之症狀及/或徵象(諸如疼痛及關節僵硬)之劑量。
如本文所用之術語「治療(treating、treated或treatment)」包括預防性(例如防治性)、緩和性及治癒性方法、用途或結果。術語「治療(treatment或treatments)」亦可指組合物,諸如醫藥組合物,或者藥劑。
在本申請案中,治療意謂一種減輕或延緩關節炎之一或多種影響或症狀的方法。治療亦可指一種減輕基礎病因而非僅僅症狀之方法。治療可為任何減輕且可為(但不限於)關節炎、關節炎之徵象或症狀的完全消除。治療可包括如藉由已知之技術所偵測,關節炎的完全好轉。此項技術中公認可用來偵測關節炎及其症狀之方法/技術包括(但不限於)例如放射學檢查、關節液抽取術、血液測試(例如偵測類風濕因子或抗CCP測試)或MRI。舉例而言,若與治療之前的個體或對照個體相比,個體之關節炎的一或多種症狀減輕約10%,則認為所揭示之方法為一種治療。因此,減輕可為約10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或其間的任何減輕量。
如本文所用,預防(prevent、preventing或prevention)意謂一種阻止、延緩、防止、避免、預先阻止、終止或阻礙關節炎發作、發生、嚴重性或再發之方法。舉例而言,若易患關節炎之個體與易患關節炎且未接受本文揭示之治療的對照個體相比,關節炎之發作、發生、嚴重性或再發或關節炎之一或多種症狀(例如疼痛、僵硬、發熱、關節發炎或關節觸痛)減輕或延緩,則認為所揭示之方法為一種預防。若易患關節炎之個體在接受本文揭示之治療後與該個體在接受治療之前的進展相比,關節炎之發作、發生、嚴重性或再發或關節炎之一或多種症狀減輕或延緩,則亦認為所揭示之方法為一種預防。因此,關節炎之發作、發生、嚴重性或再發的減輕或延緩可為約10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或其間的任何減輕量。
術語「個體」可指一種患有關節炎之脊椎動物或一種被認為需要關節炎治療之脊椎動物。個體包括溫血動物,諸如哺乳動物,諸如靈長類動物,且更佳為人類。非人類靈長類動物亦為個體。術語個體包括家養動物(諸如貓、狗等)、家畜(例如牛、馬、豬、綿羊、山羊等)及實驗動物(例如小鼠、兔、大鼠、沙鼠,天竺鼠等)。因此,本文涵蓋獸醫學用途及醫藥調配物。術語「關節炎」係指一種涉及一或多個關節發炎之關節病症或病狀。如本文所用之術語「關節炎」涵蓋多種類型及亞型之各種已知或未知病源及病因的關節炎,包括(但不限於)類風濕性關節炎、骨關節炎、感染性關節炎、牛皮癬性關節炎、痛風性關節炎及狼瘡相關之關節炎。
脂質混合物
用於本文描述之關節炎治療的脂質混合物含有餅塊、膜或粉末形式之固體脂質混合物。
在某些實施例中,磷脂及膽固醇或磷脂混合物及膽固醇在進一步加工成脂質混合物之前預先形成脂質體。
在某些實施例中,磷脂及膽固醇或磷脂混合物及膽固醇在進一步加工成脂質混合物之前不預先形成脂質體。
脂質混合物可由多種能夠形成或合併成單層或雙層結構之脂質製備。脂質混合物包括一或多種磷脂及膽固醇,實質上不含諸如三酸甘油酯之中性脂質。磷脂之實例包括(但不限於)磷脂醯膽鹼(PC)、磷脂醯甘油(PG)、磷脂醯乙醇胺(PE)、磷脂醯絲胺酸(PS)、磷脂酸(PA)、磷脂醯肌醇(PI)、卵磷脂醯膽鹼(EPC)、卵磷脂醯甘油(EPG)、
卵磷脂醯乙醇胺(EPE)、卵磷脂醯絲胺酸(EPS)、卵磷脂酸(EPA)、卵磷脂醯肌醇(EPI)、大豆磷脂醯膽鹼(SPC)、大豆磷脂醯甘油(SPG)、大豆磷脂醯乙醇胺(SPE)、大豆磷脂醯絲胺酸(SPS)、大豆磷脂酸(SPA)、大豆磷脂醯肌醇(SPI)、二棕櫚醯磷脂醯膽鹼(DPPC)、1,2-二油醯基-sn-甘油-3-磷脂醯膽鹼(DOPC)、二肉豆蔻醯磷脂醯膽鹼(DMPC)、二棕櫚醯磷脂醯甘油(DPPG)、二油醯磷脂醯甘油(DOPG)、二肉豆蔻醯磷脂醯甘油(DMPG)、十六烷基磷酸膽鹼(HEPC)、氫化大豆磷脂醯膽鹼(HSPC)、二硬脂醯磷脂醯膽鹼(DSPC)、二硬脂醯磷脂醯甘油(DSPG)、二油醯磷脂醯乙醇胺(DOPE)、棕櫚醯硬脂醯磷脂醯膽鹼(PSPC)、棕櫚醯硬脂醯磷脂醯甘油(PSPG)、單油醯磷脂醯乙醇胺(MOPE)、1-棕櫚醯-2-油醯基-sn-甘油-3-磷脂醯膽鹼(POPC)、聚乙二醇二硬脂醯磷脂醯乙醇胺(PEG-DSPE)、二棕櫚醯磷脂醯絲胺酸(DPPS)、1,2-二油醯基-sn-甘油-3-磷脂醯絲胺酸(DOPS)、二肉豆蔻醯磷脂醯絲胺酸(DMPS)、二硬脂醯磷脂醯絲胺酸(DSPS)、二棕櫚醯磷脂酸(DPPA)、1,2-二油醯基-sn-甘油-3-磷脂酸(DOPA)、二肉豆蔻醯磷脂酸(DMPA)、二硬脂醯磷脂酸(DSPA)、二棕櫚醯磷脂醯肌醇(DPPI)、1,2-二油醯基-sn-甘油-3-磷脂醯肌醇(DOPI)、二肉豆蔻醯磷脂醯肌醇(DMPI)、二硬脂醯磷脂醯肌醇(DSPI)。脂質可為一或多種上述脂質之混合物,或一或多種上述脂質與一或多種上文未列出之其他脂質的混合物。
在一個實施例中,脂質混合物包含諸如DOPC或DOPG之兩種磷脂之混合物。在另一個實施例中,脂質混合物
包含選自由DOPC、POPC、SPC、EPC、PEG-DSPE及DOPG組成之群之磷脂與膽固醇的混合物。在另一個實施例中,脂質混合物包含第一磷脂與第二磷脂之混合物,該第一磷脂為DOPC、POPC、SPC或EPC,且該第二磷脂為PEG-DSPE或DOPG。脂質混合物之各種例示性組合物在教示內容關於脂質混合物組合物之美國申請案第12/538,435號中有所揭示,該申請案以全文引用的方式併入本文中。
在一個實施例中,脂質混合物包含莫耳比為約(29.5%至90%):(3%至37.5%):(10%至33%)的DOPC、DOPG及膽固醇。在另一個實施例中,DOPC:DOPG:膽固醇之比率為以莫耳百分比計約(56.25-72.5):(7.5-18.75):(20-25)。在另一個實施例中,脂質混合物包含相對於脂質混合物約12莫耳%至小於約30莫耳%之膽固醇。在另一個實施例中,脂質混合物包含相對於脂質混合物約15莫耳%至約29莫耳%之膽固醇。在又一個實施例中,脂質混合物包含相對於脂質混合物約17.5莫耳%至約28莫耳%之膽固醇。
在一個實施例中,形成粒子之組分不含脂肪酸或陽離子脂質(亦即在生理pH下帶淨正電荷之脂質)。
在另一個實施例中,形成粒子之組分包括其中高度水合之可撓性中性聚合物之長鏈附接於磷脂分子的親水性聚合物。不受任何理論束縛,該親水性聚合物可使脂質體穩定且使在活體內之循環時間更長。親水性聚合物之實例包括(但不限於)分子量為約2,000至約5,000道爾頓(dalton)之聚乙二醇(PEG)、甲氧基PEG(mPEG)、神經節苷脂GM1、聚唾液酸、聚乳酸(亦稱為聚交酯)、聚乙醇酸(亦稱為聚乙
交酯)、聚乳酸聚乙醇酸、聚乙烯醇、聚乙烯吡咯啶酮、聚甲基噁唑啉、聚乙基噁唑啉、聚羥乙基噁唑啉、聚羥丙基噁唑啉、聚天冬醯胺、聚羥丙基甲基丙烯醯胺、聚甲基丙烯醯胺、聚二甲基丙烯醯胺、聚乙烯基甲基醚、聚丙烯酸羥乙酯、衍生化纖維素(諸如羥甲基纖維素或羥乙基纖維素)及合成聚合物。
形成粒子之組分可進一步包含抗體或肽之脂質結合物,該抗體或肽當作靶向部分,使脂質體能夠特異性地結合於帶有靶分子之靶細胞。靶分子之實例包括(但不限於)表皮生長因子受體(EGFR)、血管內皮生長因子受體(VEGF)、癌胚抗原(CEA)及erbB-2/neu(HER2)。
用於本文描述之關節炎治療的脂質體可藉由用於製備囊泡之習知技術產生。此等技術包括***注入法(Deamer等人,Acad.Sci.(1978)308:250)、界面活性劑法(Brunner等人,Biochim.Biophys.Acta(1976)455:322)、凍融法(Pick等人,Arch.Biochim.Biophys.(1981)212:186)、逆相蒸發法(Szoka等人,Biochim.Biophys.Acta.(1980)601:559 71)、超音波處理法(Huang等人,Biochemistry(1969)8:344)、乙醇注入法(Kremer等人,Biochemistry(1977)16:3932)、擠壓法(Hope等人,Biochim.Biophys.Acta(1985)812:55 65)、法式壓力法(French press method)(Barenholz等人,FEBS Lett.(1979)99:210)及Szoka,F.,Jr.等人,Ann.Rev.Biophys.Bioeng.9:467(1980)中所詳述之方法。上文闡述之所有參考文獻均描述用於形成脂質體囊泡之方法及習知技術,且此等方法之描述以引用的方式併入本文中。
在一個例示性實施例中,治療劑封裝在脂質體之載運藥劑之組分中,其中該載運藥劑之組分包含實質上水性介質,實質上不含中性脂質(諸如三酸甘油酯)、非水性相(油相)、水-油乳液或含有非水性相之其他混合物。包含實質上水性介質之載運藥劑之組分提供治療劑在關節中的較久之治療功效及延長之釋放型態。相比之下,封裝在包含實質上非水性介質(例如大豆油介質)之載運藥劑之組分中的治療劑具有更快的釋放型態及較短的治療效能(Bias等人,Sustained-Release Dexamethasone Palmitate-Pharmacokinetics and Efficacy in Patients with Activated Inflammatory Osteoarthritis of the Knee.Clin Drug Invest 2001;21(6):429-436)。
在此實施例中,脂質混合物包含一或多種未預先形成脂質體之脂質。脂質混合物可藉由將脂質溶解於適合有機溶劑(包括(但不限於)乙醇、甲醇、第三丁醇、***及氯仿)中且藉由加熱、真空蒸發、氮氣蒸發、凍乾或溶劑移除之其他習知方式乾燥來製備。
殺菌後,脂質溶液與治療劑混合且凍乾形成粉末或塊。一般地,添加至少一種低溫保護劑劑及至少一種緩衝劑以有效地凍乾類固醇-脂質混合物。
低溫保護劑包括(但不限於)甘露糖醇、甘油、右旋糖、蔗糖及/或海藻糖。一種例示性低溫保護劑為甘露糖醇。
緩衝劑包括(但不限於)二水合磷酸二氫鈉及無水磷酸氫二鈉。
下文描述脂質混合物製備之一些實例以展示脂質混合物製備之方法,因為該等方法與本發明有關。
治療劑
治療劑可為類固醇溶液、非類固醇消炎藥(NSAID)(諸如吲哚美辛)、改善病情之抗風濕藥物(DMARD)或上述兩者或超過兩者之組合,以及上述一或多者與本文中未特定列出之其他成分或化合物的組合。DMARD包括小分子藥劑,諸如甲胺喋呤、來氟米特(leflunomide)、柳氮磺胺吡啶(sulfasalazine)、環磷醯胺(cyclophosphamide)、硫唑嘌呤(azathioprine)、環孢菌素A(cyclosporin A)、d-青黴胺(d-penicillamine)、抗瘧藥(例如羥氯奎(hydroxychloroquine))。DMARD亦包括生物物質,諸如腫瘤壞死因子a(TNF-a)拮抗劑(例如依那西普,商標名Enbrel,可購自Wyeth Pharmaceuticals,Inc.,Collegeville,USA;阿達木單抗(Adalimumab),商標名HUMIRA,可購自Abbott Laboratories,Abbott Park,Illinois,USA)、介白素-1受體拮抗劑、介白素-6受體拮抗劑、抗CD20單株抗體、CTLA-4-Ig、RGD肽及其類似物。
在一例示性實施例中,治療劑為實質上水溶性類固醇溶液,諸如DSP。在另一個例示性實施例中,治療劑為實質上水溶性NSAID,諸如吲哚美辛之醫藥學上可接受之鹽。在又一個例示性實施例中,治療劑為實質上水溶性DMARD,諸如甲胺喋呤之醫藥學上可接受之鹽或TNF-a拮抗劑。在又一個例示性實施例中,治療劑不共價鍵結於磷脂或脂肪酸,諸如棕櫚酸酯。
一或多種治療劑可與醫藥學上可接受之賦形劑及適於醫藥調配(其包括用於人類及動物用途之調配物以及用於研究、實驗及相關用途之調配物)之其他成分組合。在一些實施例中,使用檸檬酸鹽緩衝液,較佳為檸檬酸鈉。在其他實施例中,使用螯合劑,較佳為EDTA。
水溶性類固醇包括任何天然存在之類固醇激素、合成類固醇及其衍生物。水溶性類固醇包括(但不限於)可體松(cortisone)、氫化可體松(hydrocortisone)、潑尼松龍(prednisolone)、甲基潑尼松龍(methylprednisolone)、潑尼松(prednisone)、***磷酸鈉(dexamethasone sodium phosphate,DSP)、氫化可體松-17-戊酸鹽、氟可體松(fluorocortisone)、氟氫可體松(fludrocortisone)、對氟米松(paramethasone)及依普利酮(eplerenone)。在一個實例中,水溶性類固醇為DSP。舉例而言,約2mg/mL至約100mg/mL之DSP溶液可用於復原脂質混合物。
水溶性類固醇之醫藥學上可接受之鹽包括由無毒的無機或有機鹼形成之無毒鹽。舉例而言,無毒鹽可用諸如鹼金屬或鹼土金屬氫氧化物(例如鉀、鈉、鋰、鈣或鎂)之無機鹼或用諸如胺及其類似物之有機鹼形成。
水溶性類固醇之醫藥學上可接受之鹽亦包括由無毒的無機或有機酸形成之無毒鹽。有機及無機酸之實例為鹽酸、硫酸、磷酸、乙酸、丁二酸、檸檬酸、乳酸、順丁烯二酸、反丁烯二酸、棕櫚酸、膽酸、雙羥萘酸、黏液酸、D-麩胺酸、戊二酸、乙二醇酸、鄰苯二甲酸、酒石酸、月桂酸、硬脂酸、水楊酸、山梨酸、苯甲酸及其類似物。
持續釋放組合物
在本文描述之關節炎治療中採用之持續釋放組合物實質上不含晶體懸浮液。在一個實施例中,持續釋放組合物中存在不足0.1%之晶體懸浮液。在另一個實施例中,持續釋放組合物中不存在晶體懸浮液。持續釋放組合物包含以下各物之組合:a)包含磷脂或磷脂混合物及膽固醇之脂質體;及b)一或多種治療劑,其中該等脂質體處於水性懸浮液中。在一些例示性實施例中,脂質混合物基本上由一或多種磷脂及膽固醇作為脂質組分組成。在其他例示性實施例中,脂質混合物基本上由磷脂醯膽鹼脂質、磷脂醯甘油脂質及膽固醇組成。在其他例示性實施例中,脂質混合物可含有(除磷脂醯膽鹼、磷脂醯甘油及膽固醇脂質之外)防腐劑、低溫保護劑或其組合。
在一些實施例中,持續釋放組合物進一步包含至少一種醫藥學上可接受之賦形劑、稀釋劑、媒劑、載劑、用於活性成分之介質、防腐劑、低溫保護劑或其組合。
在一實施例中,本發明之持續釋放組合物藉由製造脂質混合物且用治療劑復原該脂質混合物形成水性懸浮液來製備。
在另一個實施例中,本發明之持續釋放組合物藉由在製備脂質混合物期間將治療劑添加在脂質混合物中,接著與一或多種低溫保護劑凍乾形成粉末來製備。
在一例示性實施例中,持續釋放組合物包含效能相當於約2mg劑量至約8mg劑量***之水溶性類固醇。舉例而言,持續釋放組合物中4mg DSP之效能相當於3mg
***之效能。持續釋放組合物中10mg DSP之效能相當於7.6mg***之效能。類似地,40mg甲基潑尼松龍乙酸鹽之效能相當於7.5mg***之效能。
本文描述之持續釋放組合物可用於治療罹患關節炎(諸如類風濕性關節炎)之個體。
在一個實施例中,持續釋放組合物中約50%至約95%治療劑呈非締合形式(亦即約5%至約50%治療劑呈締合形式)。在另一個實施例中,持續釋放組合物中約60%-90%治療劑呈非締合形式。術語「呈非締合形式之治療劑」係指經由凝膠過濾可與持續釋放組合物之磷脂/膽固醇部分分離之治療分子。
在一個實施例中,組合之磷脂及膽固醇與治療劑之重量比為約(5-80):約1。在另一個實施例中,組合之磷脂及膽固醇與治療劑之重量比為(5-40):1。
治療關節炎之方法
本發明係有關治療個體之關節炎之方法,該方法包含向需要該治療之個體投與有效量之如本文所描述之持續釋放組合物,藉此減輕個體之關節炎的症狀及/或徵象。
持續釋放組合物經調配以適於IA、肌肉內或皮下投與。關節內注射包含以下步驟:1)確認治療關節之適當注射部位且作記號;2)使用無菌技術將注射部位殺菌且視情況提供局部麻醉劑;3)在注射部位將針***關節間隙中。針***可視情況在超音波引導下執行。吸出少量滑液以證實針尖在關節間隙內;4)將藥物注入關節間隙中。
本發明之持續釋放組合物之劑量可由熟習此項
技術者根據實施例確定。單位劑型或多個劑型均涵蓋於此發明,各自在特定臨床配置下提供優點。根據本發明,持續釋放組合物的實際量可根據有待治療之個體之年齡、體重、狀況、關節類型而改變且取決於醫學專業人員之判斷。
用於IA注射之DSP之劑量視患者之病狀及關節大小而定。在一例示性實施例中,DPS之劑量為每次IA注射約0.2mg至約6mg。在另一個例示性實施例中,對於大的關節,諸如膝關節,DPS之劑量為每次IA注射約2mg至約4mg。在又一個例示性實施例中,對於小的關節,諸如指節間關節,DPS之劑量為每次IA注射約0.8mg至約1mg。
在一例示性實施例中,每次IA注射吲哚美辛之劑量為約5mg至約30mg。在另一個例示性實施例中,每次IA注射吲哚美辛之劑量為約10mg至約25mg。在又一個例示性實施例中,每次IA注射吲哚美辛之劑量為約15mg至約20mg。
在一例示性實施例中,每次IA注射甲胺喋呤之劑量為約1mg至約15mg。在另一個例示性實施例中,每次IA注射甲胺喋呤之劑量為約5mg至約12.5mg。在又一個例示性實施例中,每次IA注射甲胺喋呤之劑量為約7.5mg至約10mg。
IA注射之頻率在每日一次、每三至五天一次、每週一次或每兩至三週一次的範圍內。
以下實例將用於進一步展示本發明,然而同時不對本發明構成任何限制。相反地,應清楚地瞭解,在閱讀本文之描述後,熟習此項技術者可想到,對於各種實施例,在
不悖離本發明之精神的情況下常可採用其修改及等效物。除非另有說明,否則在以下實例中描述之研究期間,遵循習知程序。出於例示性目的,下文描述一些程序。
實例1:脂質混合物之製備
藉由溶劑注入法製備脂質混合物。包括DOPC、DOPG及膽固醇之脂質以67.5:7.5:25之莫耳比組合且在燒瓶中在約40℃下溶解於99.9%乙醇中。使用桌上型超音波浴槽進行脂質溶解。
藉由蠕動泵以100mL/min將溶解之脂質溶液添加至1.0mM磷酸鈉溶液中,且混合兩種溶液。接著使脂質混合物通過孔徑為0.2μm之聚碳酸酯膜6-10次。形成脂質體(或大的多層囊泡(MLV))且平均囊泡直徑為約120-140nm(由Malvern ZetaSizer Nano ZS-90(Malvern Instruments Ltd,Worcestershire,UK)量測)。
藉由具有Millipore Pellicon 2微型超濾模組Biomax-100C(0.1m2)(Millipore Corporation,Billerica,MA,USA)之切向流動過濾系統透析及濃縮脂質體混合物,且接著使用0.2μm無菌過濾器殺菌。
藉由磷分析法定量過濾之脂質體混合物之脂質濃度,且用低溫保護劑2%甘露糖醇調配脂質體混合物,且接著再次使用0.2μm無菌過濾器殺菌。經殺菌之脂質體混合物接著無菌填充至小瓶中進行凍乾。
實例2:DSP持續釋放組合物之製備
藉由將實例1中描述之脂質體混合物與包含DSP(13.2mg/ml)及檸檬酸鈉(4mg/ml)之DSP溶液混合,接
著凍乾來製備持續釋放組合物。
凍乾之DSP-脂質體塊用300μl生理食鹽水復原,其中DSP之濃度為6.6mg/ml。凍乾之DSP-脂質體塊進一步用生理鹽水稀釋,形成如表1中所示之持續釋放組合物,其中在持續釋放組合物1中DSP之濃度為1mg/ml且在持續釋放組合物2中為1.4mg/ml。
實例3. 用於治療關節炎之持續釋放組合物之單次注射
使用路易斯大鼠(Lewis rat)對持續釋放組合物對關節炎之影響進行活體內評估。研究中使用16隻8週齡之雌性大鼠。大鼠之平均體重為約180至約200公克。
為誘發關節炎,第0天用200μg在弗氏不完全輔劑(Freund's incomplete adjuvant)(可購自Sigma Chemical Co.,USA)中乳化之牛II型膠原(4mg/ml,儲備於10mM乙酸中,可購自Elastin Products,Owensville,USA)對各大鼠進行免疫接種且接著在第7天再次進行。第16天為觀察到關節炎症狀之第一天且定義為誘發性關節炎之發作。
實驗研究中之所有大鼠在此研究期間始終自由地取用飲用水及食物。
該等大鼠隨機分成以下4個研究組:
第1組:4隻大鼠每個爪各接受100μl生理食鹽水(圖1-8中標記為「生理食鹽水對照」)
第2組:4隻大鼠每個爪各接受100μl游離DSP,其中DSP之濃度為1mg/ml(圖1-8中標記為「游離DSP_1mg/ml」。
第3組:4隻大鼠每個爪各接受100μl持續釋放組合物1,其中DSP之濃度為1mg/ml(圖1-4中標記為「TLC399_1mg/ml」且圖5-8中標記為「TLC399_I 1mg/ml」。
第4組:4隻大鼠每個爪各接受100μl持續釋放組合物2,其中DSP之濃度為1.4mg/ml(圖1-4中標記為「TLC399_1.4mg/mg」且圖5-8中標記為「TLC399_II 1.4mg/ml」)。
將對照或DSP調配物投與至大鼠兩個後爪,僅在第19天IA注射一次。投與至各爪之DSP劑量概述於表2中。
在14天研究期內,針對以下結果,一週檢查大鼠3次:
˙體重減輕,其為用於評估關節炎嚴重程度之參數之一。
˙臨床目測關節炎評分,其為與關節炎嚴重程度相關聯之目測評分。使用每個爪之關節指數將其分級,在0至4範圍內(0=足墊上無水腫或紅斑;1=足墊上輕微水腫及紅斑;2=足墊上輕度水腫及紅斑;3=整個足墊及足踝上中度水腫及紅
斑;4=足踝、足及趾上重度水腫及關節僵化)。各大鼠之臨床目測關節炎評分為兩個後爪之關節指數之和,滿分為8。
˙後爪體積及腫脹。藉由UGO器官充滿度測量器(Plethysmometer)7149量測系統量測後爪體積。最終體積數據用平均體重(ml/kg)校正,且水腫定義為在測量當天,相對於第0天,爪體積增加。
結果:
圖1展示4組大鼠中體重變化。在全部4組大鼠中第16天均觀察到體重減輕,此符合關節炎之發作。體重減輕自第16天持續至第19天。
第19天IA注射後,與生理食鹽水及游離DSP組相比,在持續釋放組合物1及持續釋放組合物2組中觀察到更顯著的重量減輕。重量減輕可能由類固醇之已知副作用一食慾缺乏引起。因為DSP以較慢速率自持續釋放組合物釋放,所以類固醇之副作用(食慾缺乏)持續較久。因此,在接受持續釋放組合物之組中觀察到更明顯的重量減輕。
圖2展示4組大鼠中臨床目測關節炎評分之變化。在IA注射之前,生理食鹽水組之平均評分為3.75,游離DSP及持續釋放組合物2組為4.0,且持續釋放組合物1組為4.25。
IA注射後24小時,除了生理食鹽水組外之所有組的評分均降至1以下。
對於游離DSP組,評分在IA注射48小時後緩慢增加。關節炎症狀變得更嚴重且評分在第26天達到4.5。
持續釋放組合物1及持續釋放組合物2組中之大
鼠在隨後4天未展示關節炎症狀,其中第23天及第24天評分為0。第26天,持續釋放組合物1中之三隻大鼠出現輕度關節炎症狀,平均評分為1.5,而持續釋放組合物2組中無大鼠具有任何復發症狀,其中評分保持為0。第26天游離DSP組中之大鼠具有嚴重的關節炎症狀且評分為4.5。第30天,持續釋放組合物1組中之大鼠出現嚴重關節炎,評分超過4,而持續釋放組合物2組中之大鼠具有輕度關節炎,評分為1.5。
參看圖3及圖4,第19天IA注射後,第20天所有4組中爪腫脹體積均下降。生理食鹽水組中爪腫脹體積暫時下降可能歸因於關節中發炎因子被生理食鹽水稀釋。
對於游離DSP組,IA注射之作用持續3天。第23天,兩個爪再次腫脹,厚度約7.5ml/kg。
對於持續釋放組合物1組,隨後4天爪腫脹顯著減輕。兩個爪在第25天再次變得腫脹,估算厚度約7.5ml/kg。
對於持續釋放組合物2組,隨後10天爪腫脹顯著減輕。兩個爪在約第34天再次變得腫脹,且右足踝之厚度超過8ml/kg,且左足踝為7.5ml/kg。
上述研究證明如下結論:與游離DSP相比,持續釋放組合物之單次IA注射更有效於治療實驗動物之關節炎。
實例4. 用於治療關節炎之持續釋放組合物之多次注射
此研究之設計實質上類似於實例3中描述之研究的設計,除了(a)無生理食鹽水對照組;及(b)研究藥物藉由一天一次IA注射投與,持續4天(第26天至第29天)。
結果:
圖5展示3組大鼠(游離DSP組、持續釋放組合
物1組及持續釋放組合物2組)中體重變化。在全部3組大鼠中第24天均觀察到體重減輕,此符合關節炎之發作。
自第26天至第29天之IA注射後,在3個組中觀察到更顯著的重量減輕。如實例3中所討論,重量減輕可能由類固醇之已知副作用一食慾缺乏引起。
圖6展示3組大鼠中臨床目測關節炎評分之變化。在IA注射之前,平均評分為約4.5至4.7。
對於游離DSP組,第30天評分降至3,為此研究中之最低記錄評分。關節炎徵象不久復發且在第33天變得嚴重。
對於持續釋放組合物1及持續釋放組合物2組,在第29天結束之治療後關節炎評分繼續下降且保持為零(0),直至第37天。在持續釋放組合物1組中,大鼠在第40天第一次展示復發徵象,而在持續釋放組合物2組中大鼠在第42天第一次展示復發徵象。
參看圖7及圖8,在持續4次之每日一次IA注射後,3組中兩個爪之爪腫脹體積均下降。對於游離DSP組,IA注射之作用持續1-2天。第31天,兩個爪再次腫脹,第40天達到頂峰。
對於持續釋放組合物組,隨後14天爪腫脹顯著減輕。在持續釋放組合物1組中,在第40天注意到爪腫脹之第一徵象,而在持續釋放組合物2組中,在第42天注意到爪腫脹之第一徵象。
上述研究證明如下結論:持續4次之每日一次IA持續釋放DPS注射有效治療實驗動物之關節炎。
實例5. 吲哚美辛持續釋放組合物
將吲哚美辛鈉(Hubei Heng Lu Yuan Technology Co.,Ltd,Hubei,China)用生理食鹽水溶解,至5mg/ml之最終濃度。實例1中描述之凍乾之脂質體混合物用0.3ml吲哚美辛溶液復原,產生復原體積為每一小瓶0.3ml之吲哚美辛持續釋放組合物,最終濃度為5mg/ml INN、71mg/ml DOPC、8mg/ml DOPG、13mg/ml膽固醇及50mg/ml甘露糖醇。
實例6. 用於吲哚美辛持續釋放組合物實驗研究中的膠原誘發之關節炎動物模型
使用18隻雌性路易斯大鼠(BioLASCO Taiwan Co,Ltd.,Taiwan)關於吲哚美辛持續釋放組合物對關節炎之影響進行活體內評估。研究設計及大鼠中關節炎之誘發實質上類似於實例3中之研究。
在第19天出現之臨床目測關節炎評分最高時開始關節炎治療。將18隻大鼠隨機分成三組(每組6隻大鼠):(1)對照組(無任何治療,圖9中標記為「對照」);(2)游離吲哚美辛組(每一劑量2mg/kg吲哚美辛,圖9中標記為「吲哚美辛(2mg/kg)」);及(3)吲哚美辛持續釋放組合物組(每一劑量2mg/kg吲哚美辛;圖9中標記為「吲哚美辛-BioSeizer(2mg/kg)」。自第19天至第23天,對各組中之大鼠給與無治療(對照組)、在關節炎關節周圍每日一次皮下注射游離吲哚美辛或吲哚美辛持續釋放組合物。所投與組合物中吲哚美辛之劑量在表4中列出。
表4. 游離吲哚美辛溶液及吲哚美辛持續釋放組合物之劑量。
此研究中之大鼠自研究開始增加體重,且在第12天達到頂峰。隨著關節炎之徵象出現,所有三個大鼠組中體重均下降。如圖9b中所示,第18天關節炎評分達到其最大值,平均關節炎評分在7.2-7.4之間。
第19天至第23天,第2組及第3組中關節炎症狀減輕。在第2組(游離吲哚美辛組)中,平均關節炎評分自7.4降至5,其中第20天運動機能提高且膝關節靈活性增加。第25天,在吲哚美辛治療停止2天後,關節炎之徵象(諸如僵硬、腫脹及紅斑狀關節)復發且關節炎評分達到8。
在第3組(吲哚美辛持續釋放組合物組)中,第20天,平均關節炎評分自7.6降低至5.8。關節炎評分保持低於7,直至第29天,在治療停止後治療功效延長。第3組之關節炎症狀在第30天變得嚴重。
總之,在游離吲哚美辛(第2組)或吲哚美辛持續釋放組合物(第3組)之5天治療期間,兩組中關節炎症狀均顯著地好轉。在第2組中撤除游離吲哚美辛兩天後關節炎徵象恢復,而在第3組中,在治療停止後關節炎徵象好轉持續6天。上文概述之研究結果證明如下結論:吲哚美辛持續釋放組合物比游離吲哚美辛更長時間地維持吲哚美辛在關節中之功效。
實例7. 依那西普持續釋放組合物
將實例1中描述之凍乾之脂質體混合物用0.3ml Enbrel(50mg/ml依那西普,可購自Wyeth Pharmaceuticals,Inc.,Collegeville,USA)復原,產生復原體積為每一小瓶0.3ml之依那西普持續釋放組合物。依那西普持續釋放組合物中脂質及依那西普之最終濃度為:42.8mg/ml依那西普、70.7mg/ml DOPC、8mg/ml DOPG、13mg/ml膽固醇及50mg/ml甘露糖醇。
實例8. 用於依那西普持續釋放組合物實驗研究中的膠原誘發之關節炎動物模型
使用18隻雌性路易斯大鼠(BioLASCO Taiwan Co,Ltd.,Taiwan)關於依那西普持續釋放組合物對關節炎之影響進行活體內評估。研究設計及大鼠中關節炎之誘發實質上類似於實例3中之研究,除了在第0天、第7天及第17天投與牛II型膠原。
在第23天出現之臨床目測關節炎評分最高時開始關節炎治療。將18隻大鼠隨機分成三組(每組6隻大鼠):(1)對照組(無任何治療,圖10中標記為「對照」);(2)游離依那西普組(每一劑量50mg/kg依那西普,圖10中標記為「Enbrel(50mg/kg)」);及(3)依那西普持續釋放組合物組(每一劑量50mg/kg依那西普;圖10中標記為「Enbrel-BioSeizer(50mg/kg)」。第23天及第26天,各組中之大鼠接受無治療或在關節炎關節周圍兩次皮下注射游離依那西普或依那西普持續釋放組合物。所投與組合物中依那西普之劑量在表5中列出。
表5. 游離依那西普溶液及依那西普持續釋放組
合物之劑量。
如圖10中所示,此研究中之大鼠在II型膠原免疫接種後不久即已出現關節炎徵象且在第23天達到頂峰,其中平均關節炎評分在3.6至3.8之間。
在治療期(第23天至第26天)期間,關節炎徵象在治療組(第2組及第3組)中減輕。第2組(游離依那西普組)中,第26天平均關節炎評分降至2.4,但在游離依那西普停止3天後關節炎復發。第30天,關節炎評分達到4且大鼠由於關節腫脹及僵硬而變得不動。
第3組(依那西普持續釋放組合物組)中,平均關節炎評分在第26天降低至2.2且保持低於2.5,直至第32天。第3組之關節炎症狀在第33天再次變得嚴重。
總之,在游離依那西普(第2組)或依那西普持續釋放組合物(第3組)之4天治療期間,兩組中關節炎症狀均顯著地好轉。在第2組中撤除游離依那西普三天後關節炎徵象恢復,而在第3組中,在治療停止後關節炎徵象好轉持續5天。上文概述之實驗研究結果證明如下結論:依那西普持續釋放組合物比游離依那西普更長時間地維持依那西普在關節中之功效。
實例9. 甲胺喋呤持續釋放組合物
將實例1中描述之凍乾之脂質體混合物用0.3ml
甲胺喋呤鈉(Pharmachemie BV,Inc.)復原,產生復原體積為每一小瓶0.3ml之甲胺喋呤持續釋放組合物。甲胺喋呤持續釋放組合物中脂質及甲胺喋呤之最終濃度為:2.5mg/ml甲胺喋呤、70.7mg/ml DOPC、8mg/ml DOPG、13mg/ml膽固醇及50mg/ml甘露糖醇。
實例10. 用於甲胺喋呤持續釋放組合物實驗研究中的膠原誘發之關節炎動物模型
使用18隻雌性路易斯大鼠(BioLASCO Taiwan Co,Ltd.,Taiwan)關於甲胺喋呤持續釋放組合物對關節炎之影響進行活體內評估。研究設計及大鼠中關節炎之誘發實質上類似於實例3中之研究,除了在第0天、第7天及第17天投與牛II型膠原。
在第23天出現之臨床目測關節炎評分最高時開始關節炎治療。將18隻大鼠隨機分成三組(每組6隻大鼠):(1)對照組(無任何治療,圖11a中標記為「對照」);(2)游離甲胺喋呤組(每一劑量1mg/kg甲胺喋呤,圖11a中標記為「甲胺喋呤(1mg/kg)」);及(3)甲胺喋呤持續釋放組合物組(每一劑量1mg/kg甲胺喋呤;圖11a中標記為「甲胺喋呤-BioSeizer(1mg/kg)」。第23天及第26天,對各組中之大鼠給與無治療(對照組)或在關節炎關節周圍兩次皮下注射游離甲胺喋呤或甲胺喋呤持續釋放組合物。所投與組合物中甲胺喋呤之劑量在表6中列出。
表6. 游離甲胺喋呤溶液及甲胺喋呤持續釋放組合物之劑量。
如圖11b中所示,此研究中之大鼠在II型膠原免疫接種後不久即已出現關節炎徵象且在第23天達到頂峰,其中平均關節炎評分在3.4至3.8之間。
第23天至第26天,第2組及第3組中關節炎症狀減輕。第2組(游離甲胺喋呤組)中,第26天平均關節炎評分自3.7降至1.4。第30天,甲胺喋呤治療停止4天後,大鼠變得活動減退且關節炎評分達到3.5。
在第3組(甲胺喋呤持續釋放組合物組)中,第26天,平均關節炎評分自3.4降低至1.6。關節炎評分保持在2左右,直至第35天,且隨後增加。
總之,第2組及第3組中甲胺喋呤治療使關節炎症狀好轉。在第2組中撤除游離甲胺喋呤4天後關節炎徵象恢復,而在第3組中,在治療停止後關節炎徵象好轉持續9天。上文概述之實驗研究結果證明如下結論:甲胺喋呤持續釋放組合物比游離甲胺喋呤更長時間地維持甲胺喋呤在關節中之功效。
本文中描述之要素及特徵的不同配置及組合為可能的。類似地,一些特徵及子組合適用且可在不管其他特徵及子組合下予以採用。已描述本發明之各種實施例來達到本發明之各種目標。應認識到,此等實施例僅僅為說明本發明之原理。在不悖離本發明之精神及範疇的情況下,其許多
修改及更改對熟習此項技術者而言將為顯而易見的。
Claims (25)
- 一種持續釋放組合物用以製造用於關節內、肌肉內或皮下注射至需要治療關節炎之個體的關節中的醫藥品之用途,其該持續釋放組合物包含:包含一或多種磷脂、膽固醇之脂質體,所述脂質體包含膽固醇、第一磷脂與第二磷脂,該第一磷脂為1,2-二油醯基-sn-甘油-3-磷脂醯膽鹼(DOPC)、1-棕櫚醯-2-油醯基-sn-甘油-3-磷脂醯膽鹼(POPC)、大豆磷脂醯膽鹼(SPC)或卵磷脂醯膽鹼(EPC),該第二磷脂為聚乙二醇二硬脂醯磷脂醯乙醇胺(PEG-DSPE)或二油醯磷脂醯甘油(DOPG);及一或多種治療劑,其中該等脂質體處於水性懸浮液中。
- 如請求項1之用途,其中該持續釋放組合物藉由用包含該一或多種治療劑之水溶液復原包含該一或多種磷脂及該膽固醇之凍乾之脂質混合物製備,從而形成該水性懸浮液。
- 如請求項1之用途,其中該持續釋放組合物藉由用水溶液復原凍乾的該一或多種治療劑與包含該一或多種磷脂及該膽固醇之脂質混合物的組合製備,從而形成該水性懸浮液。
- 如請求項1至3任一項之用途,其中以全部磷脂與膽固醇之混合物為基礎,DOPC:DOPG:膽固醇之莫耳百分比為約29.5%至72.5%:3%至37.5%:10%至33%。
- 如請求項1至3任一項之用途,其中以全部磷脂與膽固醇之混合物為基礎,DOPC:DOPG:膽固醇之莫耳百分比為約56.25%至72.5%:7.5%至18.75%:20%至25%。
- 如請求項1至3任一項之用途,其中該治療劑包含水溶性類固醇溶液,該水溶性類固醇溶液包含有效量之水溶性類固醇或其醫藥學上可接受之鹽。
- 如請求項6之用途,其中該水溶性類固醇為***磷酸鈉(dexamethasone sodium phosphate)。
- 如請求項6之用途,其中該水溶性類固醇溶液進一步包含緩衝劑。
- 如請求項6之用途,其中該水溶性類固醇溶液進一步包含螯合劑。
- 如請求項6之用途,其中該水溶性類固醇溶液具有相當於約2mg劑量至約8mg劑量***之效能。
- 如請求項1至3任一項之用途,其中該治療劑包含非類固醇消炎藥。
- 如請求項11之用途,其中該非類固醇消炎藥為水溶性非類固醇消炎藥。
- 如請求項12之用途,其中該水溶性非類固醇消炎藥為吲哚美辛(indomethacin)或其醫藥學上可接受之鹽。
- 如請求項13之用途,其中該吲哚美辛之醫藥學上可接受之鹽為吲哚美辛鈉。
- 如請求項13之用途,其中水溶性非類固醇消炎藥或其醫藥學上可接受之鹽的劑量為4.65至5mg/ml。
- 如請求項1至3任一項之用途,其中該治療劑包含改善病情之抗風濕藥物(DMARD)。
- 如請求項16之用途,其中該DMARD包含TNF-a拮抗劑。
- 如請求項17之用途,其中該TNF-a拮抗劑為依那西普 (etanercept)。
- 如請求項18之用途,其中依那西普之劑量為42.8mg/ml至50mg/ml。
- 如請求項17之用途,其中該TNF-a拮抗劑為Humira。
- 如請求項16之用途,其中該DMARD包含甲胺喋呤(methotrexate)或其醫藥學上可接受之鹽。
- 如請求項21之用途,其中該甲胺喋呤之醫藥學上可接受之鹽為甲胺喋呤鈉。
- 如請求項22之用途,其中甲胺喋呤或其醫藥學上可接受之鹽之劑量為2.3至2.5mg/ml。
- 如請求項1至3任一項之用途,其中該治療劑封裝在該脂質體之水性介質中。
- 如請求項1至3任一項之用途,其中該關節炎為類風濕性關節炎。
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