TW201517935A - 具有改良之安定性的(z)-2-氰基-3-羥基-丁-2-烯酸-(4’-三氟甲基苯基)-醯胺錠劑調配物 - Google Patents
具有改良之安定性的(z)-2-氰基-3-羥基-丁-2-烯酸-(4’-三氟甲基苯基)-醯胺錠劑調配物 Download PDFInfo
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- TW201517935A TW201517935A TW103142089A TW103142089A TW201517935A TW 201517935 A TW201517935 A TW 201517935A TW 103142089 A TW103142089 A TW 103142089A TW 103142089 A TW103142089 A TW 103142089A TW 201517935 A TW201517935 A TW 201517935A
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Abstract
本發明係關於含有(Z)-2-氰基-3-羥基-丁-2-烯酸-(4'-三氟甲基苯基)-醯胺的固體醫藥組成物,以及製備其之方法,利用此類組成物於治療罹患自體免疫性疾病特別指全身性紅斑狼瘡或慢性移植物抗宿主病、多發性硬化症或類風濕性關節炎之個體的方法。
Description
本發明係關於含有通常被稱為特立氟胺(Teriflunomide)之(Z)-2-氰基-3-羥基-丁-2-烯酸-(4'-三氟甲基苯基)-醯胺的醫藥組成物,以及製備其之方法,利用此類組成物於治療罹患自體免疫性疾病之個體的方法,特別指罹患全身性紅斑狼瘡或慢性移植物抗宿主病或多發性硬化症或類風濕性關節炎。
(Z)-2-氰基-3-羥基-丁-2-烯酸-(4'-三氟甲基苯基)-醯胺(特立氟胺)具有說明於式I的構造:
用於治療慢性移植物抗宿主病的(Z)-2-氰基-3-羥基-丁-2-烯酸-(4'-三氟甲基苯基)-醯胺(特立氟胺,式I)為1990年10月23日批准的美國專利4,965,276、1997年10月21日批准的美國專利5,459,163和1997年10月21日批准的美國專利5,679,709中所揭示有效用於治療特別指紅斑狼瘡之自體免疫性疾病的組成物。特立氟胺已顯示對各種免疫細胞和細胞株具有抗增生效應(Cherwinski H.M.等人,J.Pharmacol.Exp.Ther.1995,272:460~8;Prkash A.等人,Drugs 1999,58(6):1137~66;Bartlett R.R.等人,Agent Action 1991,32(1~2):10~21)。此外,其可抑制二氫乳清酸脫氫酶(DHOD),其為一種基本上用於合成嘧啶的酵素(Bruneau J-M等人,Biochem.J.1998,36:299~303)。歐洲專利1381356 B1中揭示利用特立氟胺於製造用於治療多發性硬化症的藥物,其中該藥物係被口服投藥。國際專利申請案WO 2007/118684中揭示一種含有機或無機酸以改善安定性的來氟諾胺(Leflunomide)固體醫藥組成物。該組成物與市售Arava®錠劑比較顯示來氟諾胺可被些微分解成特立氟胺。每顆含10mg來氟諾胺的錠劑可產生從0.02至0.511mg的特立氟胺。就150mg的錠劑總質量而言,特立氟胺將低於0.35%。
已發展出一種用於臨床研究的特立氟胺固體醫藥調配物。安定性試驗期間的一項觀察發現大量增加具有式II構造之2-氰基-N-(4-三氟甲基苯基)乙醯胺的降解物:
該固體醫藥調配物[特立氟胺7mg錠劑,Al/PVC泡殼包裝,儲存於25±2℃和60%相對濕度{RH}]於室溫下儲存12個月之後,其2-氰基-N-(4-三氟甲基苯基)乙醯胺的濃度可高達0.2%。其他降解物為4-三氟甲基苯胺。
本發明的目的為尋找一種不會增加2-氰基-N-(4-三氟甲基苯基)乙醯胺或4-三氟甲基苯胺(4-TFMA)濃度之缺點的特立氟胺固體醫藥調配物。
已發現一些不含二氧化矽膠體的特立氟胺固體醫藥調配物不具有增加形成2-氰基-N-(4-三氟甲基苯基)乙醯胺和4-TFMA的上述缺點。
已進一步發現該不含二氧化矽膠體的特立氟胺固體醫藥調配物加入酸性反應化合物的優點。
亦已另外發現含二氧化矽膠體的特立氟胺固體調配物加入酸性反應化合物的優點。
本發明係一種固體醫藥組成物,其含有約1至30%重量/重量(w/w)的特立氟胺,或其醫藥上可接受鹼加成鹽;約5至20%重量/重量的分解劑;約0至40%重量/重量的黏合劑;約
0.1至2%重量/重量的潤滑劑;以及其餘百分比為稀釋劑,但該固體醫藥組成物不含二氧化矽膠體。
本發明的第二態樣係一種固體醫藥組成物,其含有約1至20%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;約5至20%重量/重量的分解劑;約0至30%重量/重量的黏合劑;約0.1至2%重量/重量的潤滑劑;約1至20%重量/重量的酸性反應化合物;以及其餘百分比為稀釋劑。
本發明的第三態樣係一種固體醫藥組成物,其含有約1至20%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;約5至20%重量/重量的分解劑;約0至30%重量/重量的黏合劑;約0.1至2%重量/重量的潤滑劑;約1至20%重量/重量的酸性反應化合物;約0.1至0.5%重量/重量的二氧化矽膠體;以及其餘百分比為稀釋劑。
根據本發明所製備的固體醫藥組成物含有:a)約1至30%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;b)約5至20%重量/重量的分解劑;c)約0至40%重量/重量的黏合劑;d)約0.1至2%重量/重量的潤滑劑;以及e)其餘百分比為稀釋劑;該固體醫藥組成物不含有二氧化矽膠體。
此處所使用的名詞具有本專利說明書中所定義的意義。
「二氧化矽膠體」係次微米燻矽,亦稱為熱解矽石,其係
一種非結晶、細顆粒、低密度及高表面積的二氧化矽。主要粒徑係從5至50nm。該顆粒為不滲透並且具有從50至600m2/g的表面積。其可獲得自例如Evonik工業公司的商品Aeorsil 200 Pharma[Evonik Degussa GmbH,無機材料,WeissfrauenstraBe 9,60287 Frankfurt市,德國]或Cabot公司美國麻州Boston市總部的商品CAB-O-SIL M-5P/5DP。
「降解物」指製備單位劑型之後所產生的藥基材料。利用如技術中所習知的反相HPLC技術分析經萃取樣本的雜質和降解物。
「醫藥上可接受鹼加成鹽」係特立氟胺化合物的任何無毒性有機或無機鹼加成鹽。形成適當鹽的典型無機鹼包括氫氧化鉀、氫氧化鈉、L-離胺酸或氫氧化鈣。
「病患」意指溫血動物,舉例如大鼠、小白鼠、犬、貓、天竺鼠和靈長類動物,如人類。
「治療」或「處理」意指任何的治療包括,但不侷限於緩和症狀、暫時或永久地消除導致該症狀的原因,或預防或減慢症狀和所述疾病或病症惡化的出現。
「治療有效量」意指該化合物可有效治療該所稱疾病或病症的用量。
「立體異構物」係個別分子其原子僅在空間上具有不同方向之全部異構物的一般名詞。其包括鏡像異構物(enantio-mers)、幾何(順/反)異構物,以及具有一個以上對掌中心的化合物之異構物,其相互間並非為鏡像(非鏡像異構物;diastereoisomers)。
「特立氟胺」係化合物(Z)-2-氰基-3-羥基-丁-2-烯酸-(4'-三氟甲基苯基)-醯胺的通用名稱。可使用化學製成形式的特立
氟胺,或其可經過改變顆粒物理性質的加工。例如,該材料可藉由技術中已知的任何方法研磨。此類加工的非排他性實例包括機械研磨和噴磨。該產生顆粒可直接來自化學製備特立氟胺的加工或研磨作業之後,較佳為平均粒徑在1至100μm範圍的顆粒。較佳為使用該從1至100μm的特立氟胺顆粒製備固體醫藥組成物,其特別指在約1至10%重量/重量的特立氟胺。
已揭示特立氟胺的合成方法,以及可藉由熟習本領域之技術者所習知的方法完成。例如,1999年11月23日批准之美國專利案5,990,141中所揭示的合成方法。
本發明的進一步具體實施例係關於一種含有從約2至15%重量/重量特立氟胺以及如上述b)至e)項中所定義相同數量分解劑、黏合劑、潤滑劑和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約7至15%重量/重量分解劑以及如上述a)和c)至e)項中所定義相同數量特立氟胺、黏合劑、潤滑劑和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約15至35%重量/重量黏合劑以及如上述a)、b)、d)和e)項中所定義相同數量特立氟胺、分解劑、潤滑劑和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約0.1至1.0%重量/重量潤滑劑以及如上述a)至c)和e)項中所定義相同數量特立氟胺、分解劑、黏合劑和稀釋劑之其他成分的固體醫藥組成物。
分解劑的實例為羧甲基纖維素、低取代羥丙基纖維素、微晶纖維素、粉末纖維素、交聯羧甲基纖維素鈉、甲基纖維素、
波拉克林鉀(polacrilin potassium)、褐藻酸鈉、澱粉乙醇酸鈉,或一或多種該分解劑的混合物。
黏合劑的實例為阿拉伯膠、羧甲基纖維素、羥乙基纖維素、羥丙基纖維素、糊精、明膠、瓜爾膠、羥丙基甲基纖維素、麥芽糖糊精、甲基纖維素、褐藻酸鈉、預糊化澱粉、例如馬鈴薯、玉米或穀物的澱粉以及玉米蛋白,或一或多種該黏合劑的混合物。
潤滑劑的實例為硬脂酸鈣、棕櫚硬脂酸甘油酯、苯甲酸鈉、月桂基硫酸鈉、硬脂醯富馬酸鈉、硬脂酸、滑石粉、硬脂酸鋅和硬脂酸鎂,或一或多種該潤滑劑的混合物。
稀釋劑的實例為纖維素、醋酸纖維素、葡萄糖結合劑(dextrates)、糊精、右旋糖、果糖、1-O-α-D-吡喃葡糖基-D-甘露糖醇、棕櫚硬脂酸甘油酯、氫化植物油、白陶土、乳糖醇、乳糖單水合物、麥芽糖醇、甘露糖醇、麥芽糖糊精、麥芽糖、預糊化澱粉、氯化鈉、山梨糖醇、澱粉、蔗糖、滑石粉和木糖醇,或一或多種該稀釋劑的混合物。
本發明的進一步具體實施例係關於一種固體醫藥組成物,其含有從2至15%重量/重量特立氟胺、7至15%重量/重量選自一或多種微晶纖維素或澱粉乙醇酸鈉的分解劑、15至35%重量/重量選自一或多種羥丙基纖維素或玉米澱粉的黏合劑、0.1至1.0%重量/重量選自硬脂酸鎂的潤滑劑,以及其餘百分比為選自乳糖單水合物之稀釋劑。
本發明的進一步具體實施例係關於一種固體醫藥組成物,其含有:
A)約1至20%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;B)約5至20%重量/重量的分解劑;C)約0至30%重量/重量的黏合劑;D)約0.1至2%重量/重量的潤滑劑;E)約1至20%重量/重量的酸性反應化合物;以及F)其餘百分比為稀釋劑。
本發明的進一步具體實施例係關於一種含有從約2至15%重量/重量特立氟胺以及如上述B)至F)項中所定義相同數量分解劑、黏合劑、潤滑劑、酸性反應化合物和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約7至15%重量/重量分解劑以及如上述A)和C)至F)項中所定義相同數量特立氟胺、黏合劑、潤滑劑、酸性反應化合物和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約15至30%重量/重量黏合劑以及如上述A)、B)和D)至F)項中所定義相同數量特立氟胺、分解劑、潤滑劑、酸性反應化合物和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約0.1至1.0%重量/重量潤滑劑以及如上述A)至C)、E)和F)項中所定義相同數量特立氟胺、分解劑、黏合劑、酸性反應化合物和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約3至20%重量/重量酸性反應化合物以及如上述A)至D)和F)項中所定義
相同數量特立氟胺、分解劑、黏合劑、潤滑劑和稀釋劑之其他成分的固體醫藥組成物。
酸性反應化合物的實例為檸檬酸、醋酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富馬酸、蘋果酸、酒石酸、抗壞血酸、馬來酸、羥基馬來酸、苯甲酸、羥基苯甲酸、苯乙酸、桂皮酸、水楊酸、2-苯氧基苯甲酸、對甲苯磺酸以及磺酸,例如甲磺酸和2-羥基乙磺酸,或一或多種該酸性反應化合物的混合物。
將特立氟胺混合該分解劑、黏合劑、潤滑劑和稀釋劑成分,以獲得本發明終混合物內之特立氟胺和該其他成分的濃度,以及最後混合酸性反應化合物。於本發明進一步具體實施例中,當水被吸收入該醫藥組成物內或當少量水被加入該醫藥組成物時,含有如上述定義A)至F)成分的固體醫藥組成物顯示pH 4.5至pH 2.0。本發明的進一步具體實施例中,含有如上述定義A)至F)成分的固體醫藥組成物顯示約pH 3至約pH 2。
藉由將一顆錠劑溶解於約1ml的純水內以進行pH之測定,以pH敏感探針測定其上清液的pH。
本發明的進一步具體實施例係關於一種固體醫藥組成物,其含有:A)約1至20%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;B)約5至20%重量/重量的分解劑;C)約0至30%重量/重量的黏合劑;D)約0.1至2%重量/重量的潤滑劑;E)約1至20%重量/重量的酸性反應化合物;
F)約0.1至0.5%重量/重量的二氧化矽膠體;以及G)其餘百分比為稀釋劑。
本發明的進一步具體實施例係關於一種含有從約2至15%重量/重量特立氟胺以及如上述B)至G)項中所定義相同數量分解劑、黏合劑、潤滑劑、酸性反應化合物、二氧化矽膠體和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約7至15%重量/重量分解劑以及如上述A)和C)至G)項中所定義相同數量特立氟胺、黏合劑、潤滑劑、酸性反應化合物、二氧化矽膠體和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約15至30%重量/重量黏合劑以及如上述A)、B)和D)至G)項中所定義相同數量特立氟胺、分解劑、潤滑劑、酸性反應化合物、二氧化矽膠體和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約0.1至1.0%重量/重量潤滑劑以及如上述A)至C)、E)和G)項中所定義相同數量特立氟胺、分解劑、黏合劑、酸性反應化合物、二氧化矽膠體和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約3至20%重量/重量酸性反應化合物以及如上述A)至D)和F)、G)項中所定義相同數量特立氟胺、分解劑、黏合劑、潤滑劑、二氧化矽膠體和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約0.2至0.4%重量/重量二氧化矽膠體以及如上述A)至E)和G)項中所定義相同數量特立氟胺、分解劑、黏合劑、潤滑劑、酸性反應
化合物和稀釋劑之其他成分的固體醫藥組成物。
本發明的進一步具體實施例係關於一種含有從約0.3%重量/重量二氧化矽膠體以及如上述A)至E)和G)項中所定義相同數量特立氟胺、分解劑、黏合劑、潤滑劑、酸性反應化合物和稀釋劑之其他成分的固體醫藥組成物。
將特立氟胺混合該分解劑、黏合劑、潤滑劑、二氧化矽膠體和稀釋劑成分,以獲得於本發明終混合物內之特立氟胺和該其他成分的濃度,以及最後混合酸性反應化合物。於本發明的進一步具體實施例中,當水被吸收入該醫藥組成物內或當少量水被加入該醫藥組成物時,含有如上述定義A)至G)成分的固體醫藥組成物顯示4.5至2.0之pH值。本發明的進一步具體實施例中,含有如上述定義A)至G)成分的固體醫藥組成物顯示之pH值約pH 3至約pH 2。
為提供可形成適當單位劑型的特立氟胺調配物,根據本發明固體醫藥組成物的特立氟胺和其他成分可被混合成粉末。可利用技藝中已知的任何混合技術進行混合。該混合的進行較佳為利用高剪力混合機、V型混合機(或其他雙筒混合機)、料斗混合機或或Turbula混合振盪機。一般先在一段不添加潤滑劑的充足時間進行混合以確保能完全混合。此時,其後在一段短暫(約1~10分鐘)混合期加入潤滑劑。一旦完成該混合,藉由技藝中已知的程序製備該單位劑型。較佳為利用旋轉壓錠機或膠囊充填機製備該單位劑型。該製成的劑型可被塗佈外膜以易於吞服、專有或易於辨別的外觀及/或保護該劑型。
或者,利用下列製備特立氟胺濕顆粒以及固體醫藥組成物之其他成分的較佳方法,其步驟包括:
(a)混合特立氟胺與稀釋劑和任選的一些或全部終組成物所需的其餘賦形劑。這些其他賦形劑包括黏合劑、分解劑、潤滑劑、酸性反應化合物和二氧化矽膠體;(b)步驟(a)材料在攪拌之下加入粒化溶劑。較佳的粒化溶劑包括水、乙醇、異丙醇及其組合。粒化溶劑可加入技藝中已知的其他成分。此類添加物的實例為黏合劑、酸性反應化合物、濕潤劑、安定劑和緩衝劑。可利用技藝中已知技術粒化該溶劑。於攪拌下粒化該溶劑的較佳方法包括高剪力造粒、低剪力造粒、流化床造粒和押出造粒;(c)或者,來自步驟(b)的材料可被軋碎、研磨或篩分。然後乾燥此濕顆粒,較佳為利用空氣乾燥、流化床乾燥、烘箱乾燥或微波乾燥。較佳為在不超過約60℃的乾燥溫度之下進行乾燥;(d)此顆粒可視需要被研磨或篩分;(e)然後將該顆粒混合其他賦形劑;以及(f)將該組成物形成任選的單位劑型,較佳為錠劑或膠囊。
該製成的劑型可選擇性地被塗佈外膜以易於吞服、專有或易於辨別的外觀及/或保護該劑型。
然後利用技藝中已知的程序包裝該終劑型。就本發明而言,該包裝較佳為箔-箔冷軋型泡殼、塑膠泡殼或具有或無乾燥劑的密封瓶。較佳為使用水蒸汽滲透率低於0.25g/m2/天的泡殼包裝材料。
可利用能產生治療有效量之生物可利用化合物的任何劑型或模式投與根據本發明的固體醫藥組成物,包括口服、舌下、頰內、經皮、鼻內、肛門內、局部等。熟習製備調配物技藝的技術者可視被治療疾病的特殊性質、疾病的病程、病患的狀況和其他相關情況決定適當的投藥劑型和模式。例如,請看雷明登(Remington)製藥科學,第18版,Mack出版公司(1990)。
本發明的固體醫藥組成物可經由口服投與,例如以錠劑、喉錠、膠囊、藥片、口香糖等的劑型。
其他單位劑型可能含有可改變該劑型物理性質的其他各種材料,例如包膜錠劑。因此,錠劑或藥丸可以例如羥丙基甲基纖維素基包衣、糖、蟲膠、或其他腸溶包衣劑塗佈。
可產生治療效果的特立氟胺劑量範圍視嚴重程度、病患本身、患者的潛在性疾病和共同投與的其他藥物而定。通常,可呈現特立氟胺治療活性的劑量為每公斤病患體重0.001至約100mg/天。
本發明的固體醫藥組成物適合用於治療例如急性免疫性疾病如敗血症、過敏症、移植物對宿主反應、宿主對移植物反應;自體免疫性疾病如類風濕性關節炎、全身性紅斑狼瘡,或多發性硬化症、牛皮癬、氣喘、蕁麻疹、鼻炎和虹膜炎;癌症疾病如肺癌、白血病、卵巢癌、惡性肉瘤、卡氏(Kaposi's)肉瘤、腦膜瘤、腸道癌、淋巴結癌、腦瘤、乳癌、胰臟癌、前列腺癌或皮膚癌。
下列非限制性實例說明發明者用於製備和使用本發明之醫藥組成物的較佳方法。
將7.5mPa*s羥丙基纖維素(HPC)和檸檬酸單水合物溶解於219.3g的純水內並且至少攪拌30分鐘。不論檸檬酸的添加量,相對水的重量,終溶液內的HPC濃度為6.4%(表1)。
1.於流化床造粒機(UNI-Glatt,flap 25%,進氣溫度~23℃,振盪間隔30秒,振盪5秒)內將特立氟胺、乳糖或甘露糖醇(0C和0D)、玉米澱粉及需要時加入檸檬酸單水合物(1D和1J)混合5分鐘;2.於流化床造粒機(UNI-Glatt,flap 25~30%,進氣溫度60℃,振盪間隔60秒,振盪5秒,噴灑速率~12.5g/分鐘,霧氣壓力1bar,噴嘴直徑0.8mm)內,以HPC溶液且需要時加入檸檬酸而粒化形成的混合物。過程約25分鐘;
3.於流化床造粒機(UNI-Glatt,flap 25~30%,進氣溫度60℃,振盪間隔60秒,振盪5秒)內,將顆粒乾燥約20分鐘;4.通過1mm篩網調整顆粒大小,以及在Turbula攪拌機(2L玻璃容器)內,以微晶纖維素、澱粉乙醇酸鈉或需要時以二氧化矽膠體(實例1F~1J)潤滑5分鐘;5.加入硬脂酸鎂之後,在Turbula攪拌機(2L玻璃容器)內將該混合物再攪拌1分鐘。
於Korsch EK0單衝壓機上將終混合物壓製成錠劑。該製備固體醫藥組成物的組成列於表1、2和3。
根據實例1的製造方法製備該錠劑。該錠劑的組成列於表1、2和3。
該樣本於25℃/60%RH、30℃/65%RH、40℃/75%RH的感應密封HDPE瓶(以感應密封及配備兒童安全螺旋蓋的45mL白色寬頸瓶)內以及於40℃/75%RH的開口玻璃瓶內儲存高達6個月。儲存時瓶子為直立。
表4為具有或不含二氧化矽膠體之經檸檬酸酸化之錠劑內的2-氰基-N-(4-三氟甲基苯基)乙醯胺含量。
「RSD」意指相對標準偏差((陣列X標準偏差)100/(陣列X平均)=相對標準偏差)。
「RH」意指相對濕度;空氣-水混合物之相對濕度被定義為混合物內水蒸汽分壓對水在規定溫度之飽和蒸汽壓的比例。
於開始(第0個月)、第1、3和6個月之後測定各批中的4件樣本。
表5為含二氧化矽膠體、經檸檬酸酸化之錠劑內的2-氰基-N-(4-三氟甲基苯基)乙醯胺含量。
於開始(第0個月)、第1、3和6個月之後測定各批中的4件樣本。僅顯示受測樣本的平均值和RSD。
與含二氧化矽膠體的特立氟胺錠劑(實例0B)比較,在上述儲存條件之下,於HDPE瓶內儲存3或6個月之後,含25mg檸檬酸之含有或不含二氧化矽膠體的特立氟胺錠劑(實例1C、1D、1I、1J),以及不含檸檬酸並且無二氧化矽膠體潤滑的特立氟胺錠劑(實例0A)顯示其2-氰基-N-(4-三氟甲基苯基)乙醯胺的形成明顯降低。在感應密封HDPE瓶內,檸檬酸的安定效應於存在二氧化矽膠體之下更為明顯。
藉由下列的梯度高效液相層析儀(HPLC)測定特立氟胺、2-氰基-N-(4-三氟甲基苯基)乙醯胺和4-TFMA:固定相:Purospher STAR RP18e(3um)
管柱材料:不銹鋼
管柱長度:125mm
管柱內徑:4.0mm
管柱的平衡:管柱必需在1.0mL/分鐘的流速之下以流動相B潤洗至少15分鐘。
藉由玻璃瓶內置入50mmol(4.2g)醋酸鈉、50mmol(2.9g)氯化鈉作為流動相以及添加1000mL水的方法製備緩衝液。利用pH測量計,以冰醋酸將pH調節至6.5。
流速:1.0mL/分鐘
預期壓降:220bar
注液量:10μL
自動取樣器溫度:自動取樣溫度設定於+15℃
管柱溫度:烘箱溫度設定於+20℃
偵測:249mn(UV)
典型通報時間:25分鐘
典型總運轉時間:30分鐘
特立氟胺 約15.0分鐘
2-氰基-N-(4-三氟甲基苯基)乙醯胺 約19.3分鐘
4-TFMA 約19.8分鐘
藉由將一顆錠劑懸浮於約1ml的純水內以測定其pH。於錠劑被分解及固形物沈澱之後,以pH敏感探針測定上清液的pH。以兩次個別錠劑的平均值作為錠劑的pH(請看表2和3)。
根據實例1的製造方法製備該錠劑。錠劑的組成列於表1。
在附加安定性試驗中,將該樣本於40℃/75%RH的感應密封HDPE瓶(以感應密封及配備兒童安全螺旋蓋的60mL白色圓形寬頸瓶)內儲存6個月。儲存時瓶子為直立。
藉由HPLC(利用上述的方法)分析錠劑的相關雜質。
具有或不含二氧化矽膠體之錠劑於40℃/75%RH儲存6個月之後,2-氰基-N-(4-三氟甲基苯基)乙醯胺和4-TFMA含量列於表6。
與含二氧化矽膠體的特立氟胺錠劑(實例0B和0C)比較,在上述儲存條件之下於HDPE瓶內儲存6個月之後,不含二氧化矽膠體潤滑的特立氟胺錠劑(實例0A和0D)顯示其2-氰基-N-(4-三氟甲基苯基)乙醯胺的形成明顯降低。與經二氧化矽膠體潤滑的錠劑(實例0B和0C)比較,不含二氧化矽膠體的錠劑(實例0A和0D)明顯降低更多4-TFMA的形成。
藉由述於實例2的梯度高效液相層析儀(HPLC)測定特立氟胺、2-氰基-N-(4-三氟甲基苯基)乙醯胺和4-TFMA。
Claims (17)
- 一種固體醫藥組成物,含有a)1至30%重量/重量的特立氟胺(Teriflunomide),或其醫藥上可接受鹼加成鹽;b)5至20%重量/重量的分解劑;c)0至40%重量/重量的黏合劑;d)0.1至2%重量/重量的潤滑劑;以及e)其餘百分比為稀釋劑;但該固體醫藥組成物不含有二氧化矽膠體。
- 如申請專利範圍第1項之固體醫藥組成物,其中該分解劑係選自由羧甲基纖維素、低取代羥丙基纖維素、微晶纖維素、粉末纖維素、交聯羧甲基纖維素鈉、甲基纖維素、波拉克林鉀(polacrilin polassium)、褐藻酸鈉、澱粉乙醇酸鈉所構成的群組,或一或多種該分解劑之混合物。
- 如申請專利範圍第2項之固體醫藥組成物,其中該分解劑係選自由低取代羥丙基纖維素、微晶纖維素、粉末纖維素、交聯羧甲基纖維素鈉、澱粉乙醇酸鈉所構成的群組,或一或多種該分解劑之混合物。
- 如申請專利範圍第1項之固體醫藥組成物,其中該黏合劑係選自由阿拉伯膠、羧甲基纖維素、羥乙基纖維素、羥丙基纖維素、糊精、明膠、瓜爾膠(guar gum)、羥丙基甲基纖維素、麥芽糖糊精、甲基纖維素、褐藻酸鈉、預糊化澱粉、馬鈴薯澱粉、玉米澱粉或穀物澱粉以及玉米蛋白所構成的群組,或一或多種該黏合劑之混合物。
- 如申請專利範圍第4項之固體醫藥組成物,其中該黏合劑係選自由羥丙基纖維素、羥丙基甲基纖維素、預糊化澱粉、例如馬鈴薯澱粉、玉米澱粉或穀物澱粉之澱粉所構成的群組,或一或多種該黏合劑之混合物。
- 如申請專利範圍第1項之固體醫藥組成物,其中該潤滑劑係選自由硬脂酸鈣、棕櫚硬脂酸甘油酯、苯甲酸鈉、月桂基硫酸鈉、硬脂醯富馬酸鈉、硬脂酸、滑石粉、硬脂酸鋅和硬脂酸鎂所構成的群組,或一或多種該潤滑劑之混合物。
- 如申請專利範圍第6項之固體醫藥組成物,其中該潤滑劑係選自由硬脂醯富馬酸鈉和硬脂酸鎂所構成的群組,或一或多種該潤滑劑之混合物。
- 如申請專利範圍第1項之固體醫藥組成物,其中該稀釋劑係選自由纖維素、醋酸纖維素、葡萄糖結合劑(dextrates)、糊精、右旋糖、果糖、1-O-α-D-吡喃葡糖基-D-甘露糖醇、棕櫚硬脂酸甘油酯、氫化植物油、白陶土、乳糖醇、乳糖單水合物、麥芽糖醇、甘露糖醇、麥芽糖糊精、麥芽糖、預糊化澱粉、氯化鈉、山梨糖醇、澱粉、蔗糖、滑石粉和木糖醇所構成的群組,或一或多種該稀釋劑之混合物。
- 如申請專利範圍第8項之固體醫藥組成物,其中該稀釋劑係選自由乳糖、乳糖單水合物、甘露糖醇和澱粉所構成的群組,或一或多種該稀釋劑之混合物。
- 一種固體醫藥組成物,含有 a)1至20%重量/重量的特立氟胺,或其醫藥上可接受鹼加成鹽;b)5至20%重量/重量的分解劑;c)0至30%重量/重量的黏合劑;d)0.1至2%重量/重量的潤滑劑;e)1至20%重量/重量的酸性反應化合物,其中該酸性反應化合物係選自由檸檬酸、醋酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富馬酸、蘋果酸、酒石酸、抗壞血酸、馬來酸、羥基馬來酸、苯甲酸、羥基苯甲酸、苯醋酸、桂皮酸、水楊酸、2-苯氧基苯甲酸、對甲苯磺酸、磺酸、甲磺酸和2-羥基乙磺酸、或一或多種該酸性反應化合物之混合物所構成的群組;f)其餘百分比為稀釋劑。
- 如申請專利範圍第10項之固體醫藥組成物,其中該分解劑係選自由羧甲基纖維素、低取代羥丙基纖維素、微晶纖維素、粉末纖維素、交聯羧甲基纖維素鈉、甲基纖維素、波拉克林鉀、褐藻酸鈉、澱粉乙醇酸鈉所構成的群組,或一或多種該分解劑之混合物。
- 如申請專利範圍第10項之固體醫藥組成物,其中該黏合劑係選自由阿拉伯膠、羧甲基纖維素、羥乙基纖維素、羥丙基纖維素、糊精、明膠、瓜爾膠、羥丙基甲基纖維素、麥芽糖糊精、甲基纖維素、預糊化澱粉、褐藻酸鈉、如馬鈴薯澱粉、玉米澱粉或穀物澱粉之澱粉、以及玉米蛋白所構成的群組,或一或多種該黏合劑之混合物。
- 如申請專利範圍第10項之固體醫藥組成物,其中該潤滑劑係選自由硬脂酸鈣、棕櫚硬脂酸甘油酯、苯甲酸鈉、月桂基硫酸鈉、硬脂醯富馬酸鈉、硬脂酸、滑石粉、硬脂酸鋅和硬脂酸鎂所構成的群組,或一或多種該潤滑劑之混合物。
- 如申請專利範圍第10項之固體醫藥組成物,其中該稀釋劑係選自由纖維素、醋酸纖維素、葡萄糖結合劑、糊精、右旋糖、果糖、1-O-α-D-吡喃葡糖基-D-甘露糖醇、棕櫚硬脂酸甘油酯、氫化植物油、白陶土、乳糖醇、乳糖、麥芽糖醇、甘露糖醇、麥芽糖糊精、麥芽糖、預糊化澱粉、氯化鈉、山梨糖醇、澱粉、蔗糖、滑石粉和木糖醇所構成的群組,或一或多種該稀釋劑之混合物。
- 如申請專利範圍第10項之固體醫藥組成物,其含有約0.1至0.5%重量/重量的二氧化矽膠體。
- 如申請專利範圍第10至15項之固體醫藥組成物,其當水被吸收入該醫藥組成物內或當少量水被加入該醫藥組成物時,具有從4.5至2.0的pH。
- 如申請專利範圍第1至16項之固體醫藥組成物,其被用於治療敗血症、過敏症、移植物對宿主反應、宿主對移植物反應、類風濕性關節炎、全身性紅斑狼瘡、多發性硬化症、牛皮癬、氣喘、蕁麻疹、鼻炎、虹膜炎、肺癌、白血病、卵巢癌、惡性肉瘤、卡氏肉瘤(Kaposi’s sarcoma)、腦膜瘤、腸道癌、淋巴結癌、腦瘤、乳癌、胰臟癌、前列腺癌或皮膚癌。
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2014
- 2014-04-30 US US14/265,433 patent/US20140235888A1/en not_active Abandoned
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2015
- 2015-01-08 CL CL2015000047A patent/CL2015000047A1/es unknown
- 2015-07-16 HK HK15106785.9A patent/HK1206244A1/zh unknown
- 2015-07-16 HK HK15106786.8A patent/HK1206245A1/zh unknown
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2016
- 2016-03-28 IL IL244809A patent/IL244809B/en active IP Right Grant
- 2016-10-11 US US15/290,677 patent/US20170247319A1/en not_active Abandoned
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2017
- 2017-06-13 HR HRP20170904TT patent/HRP20170904T1/hr unknown
- 2017-07-04 CY CY20171100710T patent/CY1119364T1/el unknown
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2018
- 2018-08-20 US US15/999,565 patent/US20190241505A1/en not_active Abandoned
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2019
- 2019-02-19 IL IL26491219A patent/IL264912B/en active IP Right Grant
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