TW201434468A - 新穎醫藥組成物 - Google Patents
新穎醫藥組成物 Download PDFInfo
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- TW201434468A TW201434468A TW102143365A TW102143365A TW201434468A TW 201434468 A TW201434468 A TW 201434468A TW 102143365 A TW102143365 A TW 102143365A TW 102143365 A TW102143365 A TW 102143365A TW 201434468 A TW201434468 A TW 201434468A
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- Prior art keywords
- cyclodextrin
- hydroxypropyl
- combination
- agent
- sulfobutylether
- Prior art date
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Abstract
本發明揭示一種新穎醫藥調配物,其包含N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物、該組成物於醫療上之用途及其製備方法。
Description
本發明係有關一種用於口服液之粉末(POS),其包含如下式(I)代表之N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物,已知為賽美特尼(trametinib)二甲亞碸、Mekinist®二甲亞碸、GSK1120212B,下文亦稱為化合物A:
國際申請案案號PCT/JP2005/011082(其國際申請日期為2005年6月10日);國際公告案案號WO 2005/121142(其國際公告日期為2005年12月22日)已揭示且主張N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺之未溶合之化合物(下文稱為化合物B)與其醫藥上可接受之
鹽類與溶合物之專利權,其適用為MEK活性之抑制劑,特定言之用於治療癌症,其完整揭示內容已以引用之方式併入本文中。化合物B為實例4-1化合物。化合物B可依據國際申請案案號PCT/JP2005/011082之說明製備。化合物B可依據美國專利公告案案號US 2006/0014768(公告日期2006年1月19日)之說明製備,其完整揭示內容已以引用之方式併入本文中。化合物B為實例4-1化合物。
化合物B宜呈二甲亞碸溶合物、或化合物A或賽美特尼二甲亞碸之形式。下文中,「賽美特尼(trametinib)」意指賽美特尼二甲亞碸。化合物B宜為選自下列之溶合物形式:水合物、乙酸、乙醇、硝基甲烷、氯苯、1-戊醇、異丙醇、乙二醇與3-甲基-1-丁醇。溶合物與鹽型可由熟悉此相關技術者例如:依據國際申請案案號PCT/JP2005/011082或美國專利公告案案號US 2006/0014768之說明製備。化合物A係依據美國專利公告案案號US 2006/0014768之實例4-149之說明製備。
固體口服醫藥劑型為常用於且適用於配送醫藥活性化合物之醫藥。已知此等型式有許多種,包括錠劑、膠囊、丸劑、口含錠與粉劑。
然而,商業規模上可接受之固體口服醫藥劑型之調配物並不簡單。當於活體內投藥時,每種醫藥化合物分別在其醫療藥物層面上單獨作用。此外,醫藥活性化合物(特定言之抗新生贅瘤化合物)經常與不期望之副作用相關,如:毒性(例如:基因毒性、致畸性)及不期望之身體或心理症狀。除了要在藥物之獨特化學性質與賦形劑之性質之間取得平衡以外,藥物之明確投藥量還必需足以提供達到所需之醫療藥物程度,但必需低於導致出現不可接受副作用型態時之用量,或在該特定藥物之醫療窗口範圍內。此外,該調配物與製法必需可以提供完整劑型,讓其保持完整直到使用時為止。該等劑型亦必需具有可接受之溶解與崩解性質,以提供所需之使用型態。溶解度低與/或呈溶合物形式之醫藥活性化合物成為製備高品質劑型之特殊挑戰。此等挑戰包括活體內投藥時之曝露量不足且不一致,且脫溶劑化釋出未溶合之化合物時,可能具有不良之藥效學性質。
化合物A已在多種腫瘤型態中評估,且已在具有BRAF V600-突變陽性轉移黑色素瘤之個體中,在最近之第III期試驗中顯示抗腫瘤活性。化合物A目前已發展用於單方療法及與抗癌症醫藥組合,包括細胞毒性藥物與靶向小分子抑制劑。一種新穎藥物申請案(NDA)已提交FDA核准0.5mg、1.0mg與2.0mg之化合物A錠劑。化合物A之固體劑型,明確言之0.5mg、1.0mg與2.0mg錠劑已揭示於國際申請案案號PCT/US2011/066021(其國際申請日期為2011年12月20日);國際公告案案號WO 2012/088033(其國際公告日期為2012年6月28日),且主張其專利權。
雖然所揭示之錠劑可接受用於成人,但錠劑並不適合投與化合物A給兒童或對錠劑有吞噬困難之個體。在小兒科族群中,經常需要取得粉末型之藥物,供再重組成口服懸浮液或溶液。此等粉末需要嘗試乾式掺和各種不同賦形劑與活性物質,希望提供具有良好流動性質與含量均一之粉末掺和物。
在小兒科調配物中使用化合物A還有數項挑戰。例如:藥物物質在高濕度或含水環境中傾向從二甲亞碸溶合物轉化成脫溶劑化型式,因此無法讓標準調配物提供適當物理安定性與水溶解性。此外,化合物A對光非常敏感,因此包裝法會影響該劑型之安定性。此外,已發現該等藥物具有苦味。
此等顧慮之存在將會顯著造成化合物A於活體內投藥時之副作用。
將需要提供適合投藥給小兒科族群之含化合物A之調配物。
本發明係有關一種化合物A之口服液用粉末(POS),其適合使用水再重組成。本發明亦有關一種製備好之水溶液、調配物,特定言之安定之口服醫藥調配物,其包含化合物A與水性媒劑混合。此外,本發明係有關一種製備此等調配物之方法。
圖1:圖1出示賽美特尼於各種不同溶解劑之存在下之水溶解度。
圖2:圖2出示賽美特尼從起始濃度為1mg/mL開始,以時間及與卡維松(Cavitron)濃度二者為函數之濃度變化圖形。
圖3:圖3出示賽美特尼從起始濃度為1mg/mL開始,HPMC與各種不同溶解劑對賽美特尼水溶解度之影響。
圖4:圖4出示0.05mg/mL之化合物B使用各種不同溶解劑時,以時間為函數之溶解度變化圖形。
圖5:圖5出示使用不同風味劑系統之賽美特尼溶液之活性物與對應安慰劑之間之距離數值與其區分指數。
一項具體實施例中,本發明係有關一種口服醫藥劑型,其包含化合物A,該劑型宜呈粉末形式,該劑型宜依商業規模生產。此等粉末形式有助於提供安全且有效之治療。
一項具體實施例中,本發明係有關一種已製成之水性調配物,宜指安定之口服水性醫藥調配物,其包含化合物A與賦形劑及水性媒劑混合。此等已製成之水性形式有助於提供安全且有效之治療。
本文所採用術語「口服液用粉末(POS)」意指包含醫藥賦形劑與化合物A之醫藥調配物。
化合物A與賦形劑混合之直接粉末掺和稱為口服液用粉末(POS)。在投藥前,POS係使用水性媒劑再重組成為透明或稍微有色之溶液。溶液係依據患者之體重或體表面投藥。
已發現,化合物A可能對光出現不安定性。造成無法接受之光降解程度之可能性特別重要,因為光催化之降解產物可能有毒。
一項具體實施例中,本發明係有關一種口服液用粉末(POS),其中化合物A之含量選自:約0.1% w/w,宜低於0.1% w/w,宜約0.043% w/w。此等調配物有助於提供安全且有效之治療。
一項具體實施例中,本發明係有關一種包含化合物A之口服液用粉末(POS),其中溶解劑對化合物A之比例超過100比1,宜超過1000比1,宜超過1500比1,宜約1771比1。此等調配物有助於提供安全且有效之治療。
已發現化合物A會在操作與調配期間脫溶劑化,導致形成未溶合之化合物B。化合物B溶解度遠低於化合物A,當從醫藥組成物中釋出時,會負面影響其藥效學。當與化合物A比較時,本發明調配物中未溶合之化合物B之含量宜不超過30%,宜不超過25%,宜不超過20%,宜不超過15%,宜不超過10%,宜不超過5%,宜不超過2%。此等調配物有助於提供安全且有效之治療。
已發現化合物A在活體內投藥時,曝露量及吸收力不佳。本發明口服液用粉末(POS)宜包含微粉化化合物A,其中至少90%之化合物A粒子為1至20微米,宜為2.2至10.5微米,此等調配物提供可接受之曝露/吸收型態。本發明口服液用粉末(POS)宜包含微粉化化合物A,其中至少50%之化合物A粒子為1至6微米,宜為1.5至4.3微米,此等調配物提供可接受之曝露/吸收型態。本發明口服液用粉末(POS)宜包含微粉化化合物A,其中至少10%之化合物A粒子為0.01至3.0微米,宜為0.77至1.3微米,此等調配物提供可接受之曝露/吸收型態。此等調配物有助於提供安全且有效之治療。
一項具體實施例中,本發明口服液用粉末(POS)中之化合物A未微粉化粒子之粒度分佈為90%之化合物A粒子不超過140微米,宜為120微米或以下。此等調配物提供可接受之曝露/吸收型態。此等調配物有助於提供安全且有效之治療。
本文所採用術語「改善之性質」與其衍生用語涵括採用本發明態樣之POS於活體內釋放化合物A之藥物動力學型態相較於不採用本發明態樣之調配物具有數項優點,該調配物宜由商業規模製造。改善之性質實例包括:當POS與水性媒劑混合時,可提高口服生體可用率、改善物理與化學安定性、改善光安定性、一致之藥物動力學型態、改善之藥物動力學型態、一致之溶解速率、及安定之口服醫藥調配物。
本文所採用術語「藥物」或「活性成份」與其衍生用語,除非另有說明,否則意指化合物A或N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸。
本文所採用術語「化合物B」與其衍生用語意指N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺之游離型或未鹽化與未溶合之化合物。化合物B亦指化合物A含量中游離型或未鹽化與未溶合之化合物含量。
本文所採用術語「商業規模」與其衍生用語意指其製造批量規模超過約20kg之POS,宜超過50kg,宜超過75kg,或其批量適合製造至少約10,000個POS劑量,宜至少25,000個劑量,宜至少50,000個劑量。
本文所採用術語「有效量」與其衍生用語意指研究員或臨床人員用於對其所探討之組織、系統、動物或人類誘發生物或醫學反應時之該藥物或活性成份之用量。此外,本文所採用術語「醫療有效量」意指相較於未接受此等用量之對應個體,可以使疾病、病變、或其副作用之治療、痊癒、預防或緩解出現改善之結果,或降低疾病或病變惡化之速率時之任何用量。本文所採用該術語之範圍內亦包括可有效加強正常生理功能之用量。
本文所採用術語「共同投藥」意指同時投與或依任何方式分開依序投與包含化合物A之固態或液態口服醫藥劑型、與已知適用於治療癌症之其他活性劑或劑群,包括化療法與放射處理法。本文所採用術語「其他活性劑或劑群」包括已知或已證實在投與需要治療癌症之患者時具有有利性質之任何化合物或醫療劑。本文所採用術語「其他活性劑或劑群」可與其他抗新生贅瘤劑或劑群一詞交換使用。較佳係若不同時投藥時,化合物之投藥時間彼此非常接近。此外,化合物不一定需呈相同劑型投藥,例如:其中一種化合物可利用注射法投藥,而另一種化合物則可能經口投藥。該"共同投藥"基本上宜由包含化合物A之液態
口服醫藥劑型與包含其他活性劑之第二醫藥劑型組成。該「共同投藥」基本上宜由包含化合物A之液態口服醫藥劑型、包含其他活性劑之第二醫藥劑型、與再包含另一種活性劑之第三醫藥劑型組成。
通常,任何對所治療之感受性腫瘤具有活性之抗新生贅瘤劑均可於本發明中共同投藥治療癌症。此等藥劑實例可參見V.T.Devita與S.Hellman(編輯)之「癌症原理與腫瘤處理法(Cancer Principles and Practice of Oncology)」,第6版(2001年2月15日),出版社Lippincott Williams & Wilkins Publishers。熟悉此相關技術者均可依據藥物及所涉及癌症之特定特徵來判斷適用之藥劑組合。適用於本發明之典型抗新生贅瘤劑包括(但不限於):抗微管劑,如:二萜類(diterpenoids)與長春花生物鹼類;鉑配位錯合物;烷化劑,如:氮芥、氧氮雜磷(oxazaphosphorines)、磺酸烷基酯類、亞硝基脲類、與三氮烯類;抗生素劑,如:蒽環素(anthracyclins)、放線菌素(actinomycins)與博來黴素(bleomycins);拓樸異構酶II抑制劑,如:表鬼臼毒素;抗代謝物,如:嘌呤與嘧啶類似物與抗葉酸鹽化合物;拓樸異構酶I抑制劑,如:喜樹鹼;激素類與激素類似物;訊號轉導途徑抑制劑;非受體酪胺酸激酶血管新生抑制劑;免疫醫療劑;促細胞凋亡劑;細胞循環訊號轉導抑制劑;蛋白酶體抑制劑;與癌症代謝作用抑制劑。
其他用於與本發明醫藥劑型組合或共同投藥之其他活性劑或劑群(抗新生贅瘤劑)實例為化療劑。
抗微管或抗有絲分裂劑係在細胞循環之M期或有絲分裂期間對抗腫瘤細胞之微管之針對特定階段之活性劑。抗微管劑實例包括(但不限於):二萜類與長春花生物鹼類。
衍生自天然來源之二萜類為作用在細胞循環之G2/M期之針對特定階段之抗癌劑。咸信該二萜類藉由與微管蛋白質結合而安定其β-微小管蛋白亞單位。抑制蛋白質解構即可遏止有絲分裂,隨後造成細胞死亡。二萜類實例包括(但不限於):太平洋紫杉醇(paclitaxel)與其類似物歐洲紫杉醇(docetaxel)。
太平洋紫杉醇:5β,20-環氧基-1,2α,4,7β,10β,13α-六-羥基紫杉-11-烯-9-酮4,10-二乙酸2-苯甲酸與(2R,3S)-N-苯甲醯基-3-苯基異絲胺酸之13-酯;係來自太平洋紫杉(Taxus brevifoli)之天然二萜產物,可取得TAXOL®商品之注射液。其係萜類之紫杉烷家族成員。美國已核准太平洋紫杉醇用於臨床上治療頑固性卵巢癌與乳癌。
歐洲紫杉醇(docetaxel):(2R,3S)-N-羧基-3-苯基異絲胺酸N-第三丁酯,與5β-20-環氧基-1,2α,4,7β,10β,13α-六羥基紫杉-11-烯-9-酮4-乙酸2-苯甲酸形成之13-酯,三水合物;可取得TAXOTERE®商品之注射液。歐洲紫杉醇適用於治療乳癌。歐洲紫杉醇為太平洋紫杉醇q.v.之半合成性衍生物,其係使用從歐洲紫杉之針葉萃取出之天然前體10-去乙醯基-漿果赤霉素III製備。歐洲紫杉醇之限制劑量毒性為嗜中性白血球減少症。
長春花生物鹼類係衍生自長春花植物之針對特定階段之抗新生贅瘤劑。長春花生物鹼類藉由專一性結合微小管蛋白而作用在細胞循環之M期(有絲分裂)。因此,已結合之微小管蛋白分子無法聚合形成微管。咸信有絲分裂遏止在中期,隨後細胞即死亡。長春花生物鹼類實例包括(但不限於):長春花鹼、長春新鹼與長春瑞濱。
長春花鹼(硫酸長春花鹼)可取得VELBAN®商品之注射液。儘管其可能適用為治療各種不同固體腫瘤之第二線療法,但其仍主要用於治療睪丸癌與各種不同淋巴瘤,包括霍奇金氏症;及淋巴細胞型與組織細胞型淋巴瘤。長春花鹼之限制劑量副作用為骨髓抑制性。
長春新鹼(長春花鹼(vincaleukoblastine),22-側氧基,硫酸鹽)可取得ONCOVIN®商品之注射液。長春新鹼適用於治療急性白血病,且亦已發現其可用於治療霍奇金氏症與非霍奇金氏症惡性淋巴瘤。脫髮與神經性效應為長春新鹼之最常見副作用,並會發生較輕程度之抑制骨髓與胃腸黏膜炎效應。
長春瑞濱(3’,4’-二去氫-4’-去氧-C’-去甲基長春花鹼[R-(R*,R*)-2,3-二羥基丁二酸鹽(1:2)(鹽)]),可取得酒石酸長春瑞濱注射液(NAVELBINE®)商品,其係半合成之長春花植物鹼。長春瑞濱適用於
單方劑或與其他化療劑組合,如:順鉑(cisplatin),用於治療各種不同固體腫瘤,特定言之非小細胞肺癌、晚期乳癌、與激素頑固性睪丸癌。長春瑞濱之最常見限制劑量副作用為骨髓抑制性。
鉑配位錯合物為非針對特定階段之抗癌劑,其係與DNA交互作用。鉑錯合物會進入腫瘤細胞,進行水合,並與DNA形成股內與股間交聯,造成傷害腫瘤之生物效應。鉑配位錯合物實例包括(但不限於):順鉑與卡鉑(carboplatin)。
順鉑(順式-二胺二氯鉑)可取得PLATINOL®商品之注射液。順鉑主要適用於治療轉移性睪丸癌與卵巢癌,及晚期膀胱癌。順鉑之主要限制劑量副作用為腎毒性(其可藉由供水與利尿來控制)與耳毒性。
卡鉑(二胺[1,1-環丁烷-二羧酸鉑(2-)-O,O’])可取得PARAPLATIN®商品之注射液。卡鉑主要適用於第一線及第二線治療晚期卵巢癌瘤。卡鉑之限制劑量毒性為骨髓抑制性。
烷化劑為非針對特定階段之抗癌劑且為強力之親電子物。通常,烷化劑透過與DNA分子之親核性部份基團(如:磷酸根、胺基、氫硫基、羥基、羧基與咪唑基)之烷化作用而與DNA形成共價鍵結。此等烷化法會破壞核酸功能,造成細胞死亡。烷化劑實例包括(但不限於):氮芥,如:環磷醯胺、美法侖(melphalan)、與苯丁酸氮芥(chlorambucil);磺酸烷基酯,如:白消安(busulfan);亞硝基脲,如:卡莫司汀(carmustine);與三氮烯類,如:達卡巴仁(dacarbazine)。
環磷醯胺(2-[雙(2-氯乙基)胺基]四氫-2H-1,3,2-氧氮雜磷2-氧化物單水合物)可取得CYTOXAN®商品之注射液或錠劑。環磷醯胺適用於單方劑或與其他化療劑組合用於治療惡性淋巴瘤、多發性骨髓瘤、與白血病。環磷醯胺之最常見限制劑量副作用為脫髮、噁心、嘔吐與白血病。
美法侖(4-[雙(2-氯乙基)胺基]-L-苯基白胺酸)可取得ALKERAN®商品之注射液或錠劑。美法侖(melphalan)適用於紓緩性冶療多發性骨髓瘤與卵巢之不可切除性上皮細胞癌瘤。美法侖之最常見限制劑量副作用為骨髓抑制性。
苯丁酸氮芥(4-[雙(2-氯乙基)胺基]苯丁酸)可取得LEUKERAN®商品之錠劑。苯丁酸氮芥適用於紓緩性冶療慢性淋巴性白血病與惡性淋巴瘤,如:淋巴肉瘤、巨濾泡性淋巴瘤、與霍奇金氏症。苯丁酸氮芥之最常見限制劑量副作用為骨髓抑制性。
白消安(1,4-丁二醇二甲烷磺酸鹽)可取得MYLERAN®商品之錠劑。白消安適用於紓緩性冶療慢性骨髓性白血病。白消安之最常見限制劑量副作用為骨髓抑制性。
卡莫司汀(1,3-[雙(2-氯乙基)-1-亞硝基脲])可取得BiCNU®商品之單瓶凍乾材料。卡莫司汀係呈單方劑或與其他藥劑組合,適用於紓緩性冶療腦腫瘤、多發性骨髓瘤、霍奇金氏症、與非霍奇金氏症淋巴瘤。卡莫司汀之最常見限制劑量副作用為延遲性骨髓抑制性。
達卡巴仁(5-(3,3-二甲基-1-三氮烯基)-咪唑-4-甲醯胺)可取得DTIC-Dome®商品之單瓶材料。達卡巴仁適用於治療轉移性惡性黑色素瘤,並可與其他藥劑組合用於第二線治療霍奇金氏症。達卡巴仁之最常見限制劑量副作用為噁心、嘔吐與厭食。
抗生素抗新生瘤劑為非針對特定階段之藥劑,其會與DNA結合或交聯。通常,此等作用造成穩定之DNA複合物或斷裂股,其會破壞核酸正常功能,造成細胞死亡。抗生素抗新生贅瘤劑實例包括(但不限於):放線菌素(actinomycins)(如:更生黴素(dactinomycin))、蒽環素(如:柔紅黴素(daunorubicin)與阿黴素(doxorubicin));與博來黴素(bleomycins)。
更生黴素亦稱為放線菌素D,可取得注射型COSMEGEN®商品。更生黴素適用於治療威姆氏(Wilm’s)腫瘤與橫紋肌肉瘤。更生黴素之最常見限制劑量副作用為噁心、嘔吐、與厭食。
柔紅黴素((8S-順式-)-8-乙醯基-10-[(3-胺基-2,3,6-三去氧-α-L-來蘇-哌喃己糖基)氧]-7,8,9,10-四氫-6,8,11-三羥基-1-甲氧基-5,12萘二酮鹽酸鹽)可取得微脂粒注射型之DAUNOXOME®商品或可注射之CERUBIDINE®商品。柔紅黴素適用於誘發緩解性治療急性非淋巴細胞
白血病與晚期HIV相關之卡波西氏肉瘤。柔紅黴素之最常見限制劑量副作用為骨髓抑制性。
阿黴素((8S,10S)-10-[(3-胺基-2,3,6-三去氧-α-L-來蘇-哌喃己糖基)氧]-8-乙醇醯基,7,8,9,10-四氫-6,8,11-三羥基-1-甲氧基-5,12萘二酮鹽酸鹽)可取得注射型之RUBEX®或ADRIAMYCIN RDF®商品。阿黴素主要適用於治療急性淋巴母細胞性白血病與急性骨髓母細胞性白血病,但亦為適用於治療某些固體腫瘤與淋巴瘤之成份。阿黴素之最常見限制劑量副作用為骨髓抑制性。
博來黴素係自輪枝鏈黴菌(Streptomyces verticillus)菌株單離之細胞毒性配糖肽抗生素混合物,可取得BLENOXANE®商品。博來黴素適用於呈單方劑或與其他藥劑組合,用於紓緩性治療鱗狀細胞癌、淋巴瘤、與睪丸癌瘤。博來黴素之最常見限制劑量副作用為肺部與皮膚毒性。
拓樸異構酶II抑制劑包括(但不限於):表鬼臼毒素。表鬼臼毒素係衍生自曼德拉草植物之針對特定階段之抗新生贅瘤劑。表鬼臼毒素通常在細胞中與拓樸異構酶II及DNA形成三元複合物,造成DNA股斷裂,而影響細胞循環之S與G2期。隨後會累積斷裂股及造成細胞死亡。表鬼臼毒素實例包括(但不限於):依托泊苷(etoposide)與替尼泊苷(teniposide)。
依托泊苷(4’-去甲基-表鬼臼毒素9[4,6-0-(R)-亞乙基-β-D-哌喃葡糖苷])可取得VePESID®商品之注射液或膠囊,且通常稱為VP-16。依托泊苷(etoposide)適用於呈單方劑或與其他藥劑組合,用於治療睪丸癌與非小細胞肺癌。依托泊苷之最常見副作用為骨髓抑制性。發生白血球減少之情況比血小板減少更嚴重。
替尼泊苷(4’-去甲基-表鬼臼毒素9[4,6-0-(R)-亞噻吩基-β-D-哌喃葡糖苷])可取得VUMON®商品之注射液,且通常稱為VM-26。替尼泊苷適用於呈單方劑或與其他藥劑組合,用於治療兒童之急性白血病。替尼泊苷之最常見限制劑量副作用為骨髓抑制性。替尼泊苷會同時誘發白血球減少與血小板減少。
抗代謝物新生贅瘤藥劑係針對特定階段之抗新生贅瘤劑,其藉由抑制DNA合成或抑制嘌呤或嘧啶鹼基合成而作用在細胞循環之S期(DNA合成),藉以限制DNA合成。因此無法進行S期,隨後造成細胞死亡。抗代謝物抗新生贅瘤劑實例包括(但不限於):氟尿嘧啶、胺甲蝶呤、阿糖胞苷、氫硫基嘌呤、硫鳥嘌呤與健擇(gemcitabine)。
5-氟尿嘧啶(5-氟-2,4-(1H,3H)嘧啶二酮)可取得氟尿嘧啶商品。投與5-氟尿嘧啶會抑制胸苷酸合成,且亦會進入RNA與DNA二者中。其典型結果即為細胞死亡。5-氟尿嘧啶適用於呈單方劑或與其他藥劑組合,用於治療乳房、結腸、直腸、胃與胰臟之癌瘤。5-氟尿嘧啶之限制劑量副作用為骨髓抑制性與黏膜炎。其他氟嘧啶類似物包括5-氟去氧尿苷(去氧氟尿苷(floxuridine))與5-氟去氧尿苷單磷酸。
阿糖胞苷(4-胺基-1-β-D-呋喃阿拉伯糖基-2(1H)-嘧啶酮)可取得CYTOSAR-U®商品,且通常稱為Ara-C。咸信阿糖胞苷係針對細胞之S-期,其藉由阿糖胞苷進入延長中DNA鏈之末端來抑制DNA鏈延長。阿糖胞苷適用於呈單方劑或與其他藥劑組合,用於治療急性白血病。其他胞嘧啶核苷類似物包括5-氮雜胞嘧啶核苷與2’,2’-二氟去氧胞嘧啶核苷(健擇(gemcitabine))。阿糖胞苷會誘發白血球減少、血小板減少與黏膜炎。
氫硫基嘌呤(1,7-二氫-6H-嘌呤-6-硫酮單水合物)可取得PURINTHOL®商品。氫硫基嘌呤係針對細胞之S-期,其在一種尚未明確之機轉下抑制DNA合成。氫硫基嘌呤適用於呈單方劑或與其他藥劑組合,用於治療急性白血病。氫硫基嘌呤可能在高劑量下出現骨髓抑制性與胃腸黏膜炎副作用。適用之氫硫基嘌呤類似物為硫唑嘌呤(azathioprine)。
硫鳥嘌呤(2-胺基-1,7-二氫-6H-嘌呤-6-硫酮)可取得TABLOID®商品。硫鳥嘌呤係針對細胞之S-期,其在一種尚未明確之機轉下抑制DNA合成。硫鳥嘌呤適用於呈單方劑或與其他藥劑組合,用於治療急性白血病。投與硫鳥嘌呤之最常見限制劑量副作用為骨髓抑制性,包括白血球減少、血小板減少、與貧血。然而,亦會發生胃腸副作
用,且會限制劑量。其他嘌呤類似物包括噴司他汀(pentostatin)、赤式羥基壬基腺嘌呤、磷酸氟達拉濱(fludarabine phosphate)與克拉屈濱(cladribine)。
健擇(2’-去氧-2’,2’-二氟胞嘧啶核苷單鹽酸鹽(β-異構物))可取得GEMZAR®商品。健擇(gemcitabine)係針對細胞之S-期,且會阻斷細胞通過G1/S界線之進展。健擇適用於與順鉑組合治療局部晚期非小細胞肺癌,且可單獨治療局部晚期胰臟癌。投與健擇之最常見限制劑量副作用為骨髓抑制性,包括白血球減少、血小板減少、與貧血。
胺甲蝶呤(N-[4[[(2,4-二胺基-6-蝶啶基)甲基]甲基胺基]苯甲醯基]-L-麩胺酸)可自商品取得胺甲蝶呤鈉。胺甲蝶呤係針對細胞之S-期,其藉由抑制嘌呤核苷酸與胸苷酸之合成作用所需之二氫葉酸還原酶,來抑制DNA合成、修復與/或複製。胺甲蝶呤適用於呈單方劑或與其他藥劑組合,用於治療絨毛膜癌、腦膜性白血病、非霍奇金氏症淋巴瘤、及乳房、頭、頸、卵巢與膀胱之癌瘤。投與胺甲蝶呤可能出現之副作用為骨髓抑制性(白血球減少、血小板減少、與貧血)與黏膜炎。
喜樹鹼類(包括喜樹鹼與喜樹鹼衍生物)可取得或發展成拓樸異構酶I抑制劑。咸信喜樹鹼細胞毒性活性係與其拓樸異構酶I抑制劑活性相關。喜樹鹼實例包括(但不限於):抑諾替康(Irinotecan)、托泊替康(topotecan)、及如下說明7-(4-甲基哌基-亞甲基)-10,11-伸乙基二氧-20-喜樹鹼之各種不同光學形式。
抑諾替康(Irinotecan)HCl((4S)-4,11-二乙基-4-羥基-9-[(4-哌啶基哌啶基)羰基氧]-1H-哌喃并[3’,4’,6,7]吲哚并[1,2-b]喹啉-3,14(4H,12H)-二酮鹽酸鹽)可取得CAMPTOSAR®商品之注射液。
抑諾替康係喜樹鹼之衍生物,其及其活性代謝物SN-38均會與拓樸異構酶I-DNA複合物結合。咸信拓樸異構酶I:DNA:抑諾替康或SN-38之三元複合物與複製酵素之交互作用造成無法修復之雙股斷裂,而發生細胞毒性。抑諾替康適用於治療結腸或直腸之轉移性癌症。抑諾替康HCl之限制劑量副作用為骨髓抑制性(包括嗜中性白血球減少症)與GI效應(包括下痢)。
托泊替康HCl((S)-10-[(二甲基胺基)甲基]-4-乙基-4,9-二羥基-1H-哌喃并[3’,4’,6,7]吲哚并[1,2-b]喹啉-3,14-(4H,12H)-二酮單鹽酸鹽)可取得HYCAMTIN®商品之注射液。托泊替康係喜樹鹼之衍生物,其會與拓樸異構酶I-DNA複合物結合,阻止拓樸異構酶I隨著DNA分子之扭力所造成斷裂之單股再黏接。托泊替康適用於第二線治療卵巢與小細胞肺癌之轉移性癌瘤。托泊替康HCl之限制劑量副作用為骨髓抑制性,主要為嗜中性白血球減少症。
亦值得注意的是下如式A之喜樹鹼衍生物,其包括消旋混合物(R,S)型及R與S對映異構物:
已知其化學名稱為「7-(4-甲基哌基-亞甲基)-10,11-伸乙基二氧-20(R,S)-喜樹鹼(消旋混合物)或「7-(4-甲基哌基-亞甲基)-10,11-伸乙基二氧-20(R)-喜樹鹼(R對映異構物)或「7-(4-甲基哌并-亞甲基)-10,11-伸乙基二氧-20(S)-喜樹鹼(S對映異構物)。此等化合物及相關化合物(包括其製造方法)均說明於美國專利案案號6,063,923;5,342,947;5,559,235;與5,491,237。
激素類與激素類似物為適用於治療癌症之化合物,其中激素(群)與癌症之生長及/或缺乏生長具有相關性。適用於治療癌症之激素類與激素類似物實例包括(但不限於):腎上腺皮質類固醇,如:潑尼松(prednisone)與潑尼松龍(prednisolone),其適用於治療兒童之惡性淋巴瘤與急性白血病;胺基格魯米特(glutethimide)與其他芳構酶抑制劑,如:安達美(anastrozole)、來曲唑(letrazole)、伏氯唑(vorazole)、與依西美坦
(exemestane),其適用於治療腎上腺皮質癌瘤與包含雌激素受體之激素依賴性乳房癌瘤;黃體酮,如:醋酸甲地羥孕酮,其適用於治療激素依賴性乳癌與子宮內膜癌瘤;雌激素、雄激素與抗雄激素,如:氟他胺(flutamide)、尼魯米特(nilutamide)、比卡鲁胺(bicalutamide)、醋酸環丙孕酮與5α-還原酶,如:菲那諾(finasteride)與度他雄胺(dutasteride),其適用於治療前列腺癌瘤與良性前列腺肥大;抗雌激素,如:他莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛西芬(raloxifene)、屈洛昔芬(droloxifene)、碘昔芬(iodoxyfene),及選擇性雌激素受體調節劑(SERMS),如彼等說明於美國專利案案號5,681,835;5,877,219;與6,207,716者,其適用於治療激素依賴性乳房癌瘤與其他感受性癌症;及性腺激素釋放激素(GnRH)與其類似物,其模擬釋放黃體激素(LH)與/或濾泡刺激激素(FSH),供治療前列腺癌瘤,例如:LHRH促效劑與拮抗劑,如:醋酸戈舍瑞林(goserelin acetate)與亮丙瑞林(luprolide).
訊號轉導途徑抑制劑為彼等阻斷或抑制該會激發細胞內變化之化學過程之抑制劑。本文所指之變化為細胞增生或分化。適用於本發明之訊號轉導抑制劑包括受體酪胺酸激酶、非受體酪胺酸激酶、SH2/SH3功能域阻斷劑、絲胺酸/蘇胺酸激酶、磷脂醯肌醇-3激酶、肌醇訊號轉導、與Ras致癌基因等之抑制劑。
有數種蛋白質酪胺酸激酶催化涉及細胞生長調節作用之各種不同蛋白質中特定酪胺醯基殘基之磷酸化。此等蛋白質酪胺酸激酶可廣義歸為受體或非受體激酶。
受體酪胺酸激酶為具有細胞外配體結合功能域、穿膜功能域與酪胺酸激酶功能域之穿膜蛋白質。受體酪胺酸激酶涉及細胞生長之調節作用,通常稱為生長因子受體。許多此等激酶之活化不當或失控,亦即例如:因過度表現或突變所致之激酶生長因子受體活性異常,已顯示會導致失控之細胞生長。因此此等激酶之異常活性已與惡性組織生長相關。因此此等激酶之抑制劑將可提供治療癌症之方法。生長因子受體包括例如:上皮生長因子受體(EGFr)、血小板衍生之生長因子受體(PDGFr)、erbB2、erbB4、血管內皮生長因子受體(VEGFr)、具有類似免
疫球蛋白與上皮生長因子同源功能域之酪胺酸激酶(TIE-2)、胰島素生長因子-I(IGFI)受體、巨噬細胞群落刺激因子(cfms)、BTK、ckit、cmet、纖維母細胞生長因子(FGF)受體、Trk受體(TrkA、TrkB與TrkC)、ephrin(eph)受體、與RET原致癌基因。生長受體之數種抑制劑已在發展中,且包括配體拮抗劑、抗體、酪胺酸激酶抑制劑與反義寡核苷酸。抑制生長因子受體功能之生長因子受體與製劑說明於例如:Kath,John C.之Exp.Opin.Ther.Patents(2000)10(6):803-818;Shawver等人之DDT Vol 2,No.2 1997年2月;與Lofts,F.J.等人之「作為標靶之生長因子受體(Growth factor receptors as targets)」,癌症化療法之新穎分子標靶(New Molecular Targets for Cancer Chemotherapy),Paul Workman與David Kerr編輯,倫敦CRC出版社,1994。
酪胺酸激酶不是生長因子受體激酶,稱為非受體酪胺酸激酶。用於本發明作為抗癌藥物之標靶或潛在標靶之非受體酪胺酸激酶包括cSrc、Lck、Fyn、Yes、Jak、cAbl、FAK(局部黏著斑激酶)、Brutons酪胺酸激酶、與Bcr-Abl。此等抑制非受體酪胺酸激酶功能之非受體激酶與藥劑說明於Sinh,S.與Corey,S.J.(1999)之Journal of Hematotherapy and Stem Cell Research 8(5):465-80;與Bolen,J.B.、Brugge,J.S.(1997)之Annual review of Immunology.15:371-404。
SH2/SH3功能域阻斷劑為在各種不同酵素或適體蛋白質(包括PI3-K p85亞單位、Src家族激酶、適體分子(Shc、Crk、Nck、Grb2)與Ras-GAP)中干擾SH2或SH3功能域結合性之製劑。以SH2/SH3功能域為標靶之抗癌藥物說明於Smithgall,T.E.(1995)之Journal of Pharmacological and Toxicological Methods.34(3)125-32。
絲胺酸/蘇胺酸激酶之抑制劑包括MAP激酶級聯反應阻斷劑,其包括Raf激酶(rafk)、有絲分裂素或細胞外調節激酶(MEK)、與細胞外調節激酶(ERK)之阻斷劑;與蛋白質激酶C家族成員阻斷劑,包括PKC(α、β、γ、ε、μ、λ、、ζ)之阻斷劑。IkB激酶家族(IKKa、IKKb)、PKB家族激酶、akt激酶家族成員、PDK1與TGF β受體激酶。此等絲胺酸/蘇胺酸激酶與其抑制劑說明於Yamamoto,T.、Taya,S.、Kaibuchi,
K.(1999)之Journal of Biochemistry.126(5)799-803;Brodt,P、Samani,A.與Navab,R.(2000)之Biochemical Pharmacology,60.1101-1107;Massague,J.、Weis-Garcia,F(1996)之「癌症調查(Cancer Surveys)」,27:41-64;Philip,P.A.與Harris,A.L.(1995)之「癌症治療與研究(Cancer Treatment and Research)」.78:3-27;Lackey,K.等人之Bioorganic and Medicinal Chemistry Letters,(10),2000,223-226;美國專利案案號6,268,391;Pearce,L.R等人之「自然分子生物學概論(Nature Reviews Molecular Cell Biology)」(2010)11,9-22;及Marrtinez-Iacaci,L.等人之Int.J.Cancer(2000),88(1),44-52。
本發明醫藥活性化合物宜與B-Raf抑制劑組合使用。宜為已揭示於國際申請案案號PCT/US2009/042682(國際申請日期為2009年5月4日,其完整揭示內容已以引用之方式併入本文中)中說明且主張專利權之N-{3-[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺醯胺或其醫藥上可接受之鹽。N-{3-[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺醯胺可依國際申請案案號PCT/US2009/042682之說明製備。
本發明醫藥活性化合物宜與Akt抑制劑組合使用。宜為已揭示於國際申請案案號PCT/US2008/053269(國際申請日期為2008年2月7日);國際公告案案號WO 2008/098104(國際公告日期為2008年8月14日)(其完整揭示內容已以引用之方式併入本文中)中說明且主張專利權之N-{(1S)-2-胺基-1-[(3,4-二氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-呋喃甲醯胺或其醫藥上可接受之鹽。N-{(1S)-2-胺基-1-[(3,4-二氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-呋喃甲醯胺為其中之實例224化合物,且可依據國際申請案案號PCT/US2008/053269之說明製備。
本發明醫藥活性化合物宜與Akt抑制劑組合使用。宜為已揭示於國際申請案案號PCT/US2008/053269(國際申請日期為2008年2月7日);國際公告案案號WO 2008/098104(國際公告日期為2008年8月14日)(其完整揭示內容已以引用之方式併入本文中)中說明且主張
專利權之N-{(1S)-2-胺基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲醯胺或其醫藥上可接受之鹽。N-{(1S)-2-胺基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲醯胺為其中之實例96化合物,且可依國際申請案案號PCT/US2008/053269之說明製備。N-{(1S)-2-胺基-1-[(3-氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-噻吩甲醯胺係呈鹽酸鹽型。該鹽型可由熟悉此相關技術者依據國際申請案案號PCT/US2010/022323(國際申請日期為2010年1月28日)之說明製備。
磷脂醯肌醇-3激酶家族成員之抑制劑(包括PI3-激酶、ATM、DNA-PK、與Ku之阻斷劑)亦適用於本發明。此等激酶說明於Abraham,R.T.(1996)之Current Opinion in Immunology.8(3)412-8;Canman,C.E.,Lim,D.S.(1998)之Oncogene 17(25)3301-3308;Jackson,S.P.(1997)之International Journal of Biochemistry and Cell Biology.29(7):935-8;與Zhong,H.等人之Cancer res,(2000)60(6),1541-1545。
本發明亦值得注意肌醇訊號轉導抑制劑,如:磷脂酶C阻斷劑與肌醇類似物。此等訊號轉導抑制劑說明於Powis,G.與Kozikowski A.(1994)之「癌症化療法之新穎分子標靶(New Molecular Targets for Cancer Chemotherapy)」,Paul Workman與David Kerr編輯,倫敦CRC出版社1994。
另一類訊號轉導途徑抑制劑為Ras致癌基因之抑制劑。此等抑制劑包括法哌基轉移酶、牻牛兒基-牻牛兒基轉移酶、與CAAX蛋白酶等之抑制劑,及反義寡核苷酸、核酶與免疫療法。此等抑制劑已顯示可於包含野生型突變株ras之細胞內阻斷ras活化作用,藉以具有抗增生劑之作用。Ras致癌基因之抑制作用說明於Scharovsky,O.G.、Rozados,V.R.、Gervasoni,S.I.、Matar,P.(2000)之Journal of Biomedical Science.7(4)292-8;Ashby,M.N.(1998)之Current Opinion in Lipidology.9(2)99-102;與BioChim.Biophys.Acta,(19899)1423(3):19-30。
如上述,針對受體激酶配體結合性之抗體拮抗劑亦可作為訊號轉導抑制劑。此類訊號轉導途徑抑制劑包括使用針對受體酪胺
酸激酶之細胞外配體結合性功能域之擬人化抗體。例如:Imclone C225 EGFR專一性抗體(參見Green,M.C.等人之「固體腫瘤之單株抗體療法(Monoclonal Antibody Therapy for Solid Tumors)」,Cancer Treat.Rev.,(2000),26(4),269-286);Herceptin ® erbB2抗體;與2CB VEGFR2專一性抗體(參見Brekken,R.A.等人之「單株抗VEGF抗體阻斷小鼠腫瘤生之選擇性抑制VEGFR2活性(Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice)」,Cancer Res.(2000)60,5117-5124)。
非受體激酶血管新生抑制劑亦適用於本發明。與VEGFR及TIE2相關之血管新生之抑制劑係如上述與訊號轉導抑制劑相關之說明(兩種受體均為受體酪胺酸激酶)。血管新生通常與erbB2/EGFR訊號轉導相關,因為erbB2與EGFR之抑制劑已顯示可抑制血管新生,主要針對VEGF表現。因此,非受體酪胺酸激酶抑制劑可與本發明化合物組合使用。例如:抗VEGF抗體,其無法辨識VEGFR(受體酪胺酸激酶),但可與配體結合;整合素(α、β)之小分子抑制劑,其可抑制血管新生;內皮抑素與血管增生抑制素(非RTK)亦已證明適用於與本揭示之化合物組合使用。
用於免疫療法之藥劑亦適用於與式(I)化合物組合使用。有許多種免疫法可以產生免疫反應。此等方法通常在腫瘤免疫接種之領域內。可以透過組合使用小分子抑制劑來抑制訊號轉導途徑大幅加強免疫法之效力。有關針對erbB2/EGFR之免疫/腫瘤疫苗法可參見Reilly RT等人之(2000),Cancer Res.60:3569-3576;與Chen Y,Hu D,Eling DJ,Robbins J與Kipps TJ.(1998),Cancer Res.58:1965-1971。
用於促細胞凋亡療法之藥劑(例如:bcl-2反義寡核苷酸)亦可用於本發明之組合中。Bcl-2家族蛋白質之成員可阻斷細胞凋亡。因此bcl-2之上調與化學抗性相關。已有研究顯示,上皮生長因子(EGF)刺激bcl-2家族之抗細胞凋亡成員(亦即mcl-1)。因此,設計用於下調腫瘤中bcl-2表現之方法已證實具有臨床效益,亦即Genta's G3139 bcl-2反義寡核苷酸。此等使用bcl-2之反義寡核苷酸之促細胞凋亡方法說明於
Water JS等人之(2000),J.Clin.Oncol.18:1812-1823;與Kitada S等人之(1994),Antisense Res.Dev.4:71-79。
細胞循環訊號轉導抑制劑抑制涉及控制細胞循環之分子。稱為環素依賴性激酶(CDK)之蛋白質激酶家族及其與稱為環素之蛋白質家族之交互作用控制透過真核細胞生物細胞循環之進展。透過細胞循環之正常進展需要不同環素/CDK複合物之配位活化與失活。細胞循環訊號轉導之數種抑制劑已在發展中。例如:環素依賴性激酶(包括CDK2、CDK4、與CDK6)與其抑制劑之實例說明於例如:Rosania等人之Exp.Opin.Ther.Patents(2000)10(2):215-230。此外,已有文獻說明p21WAF1/CIP1為環素-依賴性激酶(Cdk)之強力且通用之抑制劑(Ball等人之Progress in Cell Cycle Res.,3:125(1997))。已知可誘發p21WAF1/CIP1表現之化合物已涉及抑制細胞增生,且具有抑制腫瘤活性(Richon等人之Proc.Nat Acad.Sci.U.S.A.97(18):10014-10019(2000)),且包括其作為細胞循環訊號轉導抑制劑。組蛋白去乙醯化酶(HDAC)抑制劑涉及p21WAF1/CIP1之轉錄活化作用(Vigushin等人之Anticancer Drugs,13(1):1-13(Jan 2002)),且為適用於本文之細胞循環訊號轉導抑制劑。
此等HDAC抑制劑實例包括:
1.伏立諾他(Vorinostat),包括其醫藥上可接受之鹽類。Marks等人之Nature Biotechnology 25,84至90(2007);Stenger,Community Oncology 4,384-386(2007)。
伏立諾他具有如下化學結構式與名稱:
N-羥基-N'-苯基-辛烷二醯胺
2.羅米地辛(Romidepsin),包括其醫藥上可接受之鹽類。
Vinodhkumar等人之Biomedicine & Pharmacotherapy 62(2008)85-93。
羅米地辛具有如下化學結構式與名稱:
(1S,4S,7Z,10S,16E,21R)-7-亞乙基-4,21-二(丙烷-2-基)-2-氧雜-12,13-二硫雜-5,8,20,23-四氮雜雙環[8.7.6]二十三碳-16-烯-3,6,9,19,22-戊酮
3.帕比司他(Panobinostat),包括其醫藥上可接受之鹽類。Drugs of the Future 32(4):315-322(2007)。
帕比司他(Panobinostat)具有如下化學結構式與名稱:
(2E)-N-羥基-3-[4-({[2-(2-甲基-1H-吲哚-3-基)乙基]胺基}甲基)苯基]丙烯醯胺
4.丙戊酸(Valproic acid),包括其醫藥上可接受之鹽類。Gottlicher等人之EMBO J.20(24):6969-6978(2001)。
丙戊酸具有如下化學結構式與名稱:
2-丙基戊酸
5.莫克抑素(Mocetinostat)(MGCD0103),包括其醫藥上可接受之鹽類。Balasubramanian等人之Cancer Letters 280:211-221(2009)。
莫克抑素具有如下化學結構式與名稱:
N-(2-胺基苯基)-4-[[(4-吡啶-3-基嘧啶-2-基)胺基]甲基]苯甲醯胺
此等HDAC抑制劑之其他實例包括在Bertrand European Journal of Medicinal Chemistry 45,(2010)2095-2116中,特定言之下表3所示之化合物。
蛋白酶體抑制劑為阻斷蛋白酶體(其係降解蛋白質之細胞複合物)作用之藥物,如同p53蛋白質。已有數種蛋白酶體抑制劑上市或研究用於治療癌症。適用於本文之蛋白酶體抑制劑包括:
1.硼替佐米(Bortezomib)(Velcade®),包括其醫藥上可接受之鹽類。Adams J,Kauffman M(2004),Cancer Invest 22(2):304-11。
硼替佐米(Bortezomib)具有如下化學結構式與名稱。
[(1R)-3-甲基-1-({(2S)-3-苯基-2-[(吡-2-基羰基)胺基]丙烯基}胺基)丁基]二羥硼酸
2.雙硫崙(Disulfiram),包括其醫藥上可接受之鹽類。
Bouma等人之(1998)J.Antimicrob.Chemother. 42(6):817-20。
雙硫崙具有如下化學結構式與名稱。
1,1',1",1'''-[二硫烷二基雙(硫羰基次氮基)]四乙烷
3.兒茶素表沒食子酸酯(EGCG),包括其醫藥上可接受之鹽類。Williamson等人(2006年12月)The Journal of Allergy and Clinical Immunology 118(6):1369-74。
兒茶素表沒食子酸酯具有如下化學結構式與名稱。
3,4,5-三羥基苯甲酸[(2R,3R)-5,7-二羥基-2-(3,4,5-三羥基苯基)色滿-3-基]酯
4.鹽孢菌素(Salinosporamide)A,包括其醫藥上可接受之鹽類。Feling等人(2003),Angew.Chem.Int.Ed.Engl. 42(3):355-7。
鹽孢菌素A具有如下化學結構式與名稱。
(4R,5S)-4-(2-氯乙基)-1-((1S)-環己-2-烯基(羥基)甲基)-5-甲基-6-氧雜-2-氮雜雙環3.2.0庚烷-3,7-二酮
癌症代謝作用之抑制劑-許多腫瘤細胞顯示與正常組織顯著不同之代謝作用。例如:糖解速率(即葡萄糖轉化成丙酮酸之代謝過程)會提高,且所產生之丙酮酸會還原成乳酸,而非進一步於粒線體中經由三羧酸(TCA)循環進行氧化。即使在好氧條件下,此效應亦經常出現,且稱為華伯格效應(Warburg Effect)。
乳酸脫氫酶A(LDH-A)係表現在肌肉細胞中之乳酸脫氫酶之同功型,在腫瘤細胞代謝作用扮演中樞角色,其將丙酮酸還原成乳酸,然後再運出細胞外。許多腫瘤型態均顯示上調此酵素。華伯格效應中所述之葡萄糖代謝作用之變化對癌細胞之生長與增生很重要,且在異種移植模式中利用RNA-i敲低LDH-A時,已顯示會降低細胞增生與腫瘤生長。
D.A.Tennant et.al.,Nature Reviews,2010,267。
P.Leder,et.al.,Cancer Cell,2006,9,425。
癌症代謝作用抑制劑包括LDH-A之抑制劑,適合與本發明調配物組合使用。
溶解劑、表面活性劑、緩衝劑、防腐劑、甜味劑與風味劑實例係相關技藝咸了解者,此等組成份一般說明於例如:Martindale之「大藥典(The Extra Pharmacopoeia)」,倫敦Pharmaceutical Press出版(1993)及Martin(編輯)之「雷氏醫藥學(Remington's Pharmaceutical Sciences)」,及「醫藥賦形劑手冊(the Handbook of Pharmaceutical Excipients)」。
本文所採用術語「溶解劑」係一種促進藥物均勻分散並溶解於溶液中之物質(液態或固態)。溶解劑防止藥物從溶液中再結晶與沉澱。用於本發明之合適溶解劑包括(但不限於):羥丙基甲基纖維素、聚乙烯吡咯啶酮、磺基丁基醚β-環糊精(Captisol)與羥基丙基β-環糊精(卡維松(Cavitron))。亦可使用溶解劑之組合。例如:羥丙基甲基纖維素與羥基丙基β-環糊精具有良好之化合物A水溶解度。已發現聚乙二醇與丙二醇等溶解劑之缺點即在對化合物A之水溶解度極低。其在根據本發明調配物中之含量應選自佔終產物重量:約30至95%;宜約50至80%;宜約65至75%。根據本發明調配物中之溶解劑含量應佔終產物重量:約30%;宜約35%、宜約40%、宜約45%、宜約50%、宜約55%、宜約60%、宜約65%、宜約70%、宜約75%、宜約80%、宜約85%、宜約90%、與宜約95%。
本文所採用術語「表面活性劑」係可降低液體之表面張力、兩種液體之間界面張力、及液體與固體之間界面張力之表面活性劑,藉以提高藥物粒子之可濕化性,使其容易溶解。例如:合適之表面活性劑包括(但不限於):羥丙基甲基纖維素(HPMC)、聚山梨糖醇酯(polysorbate)80、聚山梨糖醇酯20與月桂基硫酸酯鈉(SLS)。較佳表面活性劑為羥丙基甲基纖維素,因為已發現其在此例中可同時作為表面活性劑與溶解劑。根據本發明調配物中之表面活性劑含量宜選自佔終產物重量:約0至5%;宜約0.5至4%、宜約0.5至2%。若存在時,根據本發明調配物中之表面活性劑含量宜選自佔終產物重量:約0.5%;宜約1%、宜約1.5%。
本文所採用術語「緩衝劑」係弱酸與其共軛鹼或弱
鹼與其共軛酸之混合物,其用於在添加少量酸或鹼時阻止pH變化。適用於本文之緩衝劑包括檸檬酸單水合物與磷酸鈉(二鹼價,無水或其組合)。根據本發明調配物中之緩衝劑總含量宜選自佔終產物重量:約5至25%;宜約8至20%、宜約10至20%。根據本發明調配物中之緩衝劑總含量宜選自佔終產物重量:約5%;宜約10%、宜約15%、宜約20%。
本文所採用術語「防腐劑」係用於液態調配物中防止細菌與/或真菌生長。例如:合適之防腐劑包括(但不限於):對羥基苯甲酸酯(甲酯、乙酯、丙酯、與丁酯)、對羥基苯甲酸鈉鹽、山梨酸鉀、苯甲酸鈉、與山梨酸。根據本發明調配物中之防腐劑總含量宜選自佔終產物重量:約0.5至4%;宜約1至3%、宜約1至2.5%。根據本發明調配物中之防腐劑總含量宜選自佔終產物重量:約0.5%;宜約1%、宜約1.5%、宜約2%。
本文所採用術語「甜味劑」係一種用於改善調配物適口性之物質(固態或液態)。例如:合適之甜味劑包括(但不限於):木糖醇錠(xylitab)、木糖醇、甘露糖醇、蔗糖、蔗糖素、糖精、甘草酸銨與甘草酸鈉、阿斯巴甜(aspartame)與山梨醇。根據本發明調配物中之甜味劑含量宜選自佔終產物重量:約5至25%;宜約8至20%、宜約10至20%。根據本發明調配物中之甜味劑含量宜選自佔終產物重量:約5%;宜約10%、宜約15%、宜約20%。
本文所採用術語「風味劑」係一種為調配物提供獨特味道與香氣之物質(液態或固態)。風味劑亦有利於改善調配物之適口性。風味劑宜為草莓風味劑。根據本發明調配物中之風味劑含量宜選自佔終產物重量:約0.5至4%;宜約1至3%、宜約1至2.5%。根據本發明調配物中之風味劑含量宜選自佔終產物重量:約0.5%;宜約1%、宜約1.5%、宜約2%。
本文所採用術語「媒劑」為一種用於將粉末再重組成為口服懸浮液或溶液之液體。媒劑必需可與調配物相容,以達成並維持安定性。例如:合適媒劑包括(但不限於):純水、注射用無菌水與點滴用無菌水。根據一項具體實施例,該媒劑係純水或無菌水。
賽美特尼之溶解度
賽美特尼於羥基丙基β-環糊精(卡維松(Cavitron))、磺基丁基醚β-環糊精(Captisol)、聚乙二醇(PEG)、與丙二醇調配物中之水溶解度示於圖1。卡維松(Cavitron)之溶解度最高,其次為磺基丁基醚β-環糊精(Captisol)。賽美特尼通常不溶於PEG或丙二醇溶液。
賽美特尼濃度
卡維松濃度與時間對賽美特尼溶解度之影響示於圖2。此實驗中,賽美特尼起始濃度為1mg/mL,經過5天後,賽美特尼濃度降至起始濃度之約7至10%。示於圖2之結果顯示,在所採用之條件下,當化合物B之起始濃度為約0.05mg/mL時,自溶液中沉澱之藥物量不顯著。
添加HPMC
圖3出示卡維松溶液中存在之HPMC會抑制賽美特尼自溶液中沉澱,而提高賽美特尼溶液之安定性。
賽美特尼之溶解型態
圖4出示賽美特尼於卡維松與磺基丁基醚β-環糊精(Captisol)溶液中以時間為函數之溶解型態。兩種溶解劑均可在25℃與60%相對濕度之儲存條件下維持溶解度及安定之溶液。
隨後,抗微生物效力試驗顯示卡維松在賽美特尼之存在下會促進真菌(霉菌)生長,需要較高之防腐劑濃度以提供微生物安定性。
調味
已知賽美特尼帶有苦味。採用Astree®電子舌頭(e-舌)分析溶液調配物之味道知覺。e-舌測定活性懸浮調配物與其對應之安慰劑之間之味道區分與近似測量值與分析圖譜。由主成分分析法(PCA)分析e-舌測定值。假設安慰劑代表理想「目標」味道型態,因為其中沒有苦味活性組成份。因此採用活性物與安慰劑調配物之間在PCA圖譜上之歐幾里得距離(euclidean distance)來定量苦味之遮蔽性或味道之近似性。距離越小表示風味劑遮蔽之效果越好,因此使活性物與安慰劑e-舌「指印」更接近。以區分指數(DI,以%表示)代表每一對調配物之感測器輸出重心之間之差
異及調配物在感測器輸出內之分散度。區分指數值越高(越接近100%),表示調配物之間相似度越低,遮蔽性越差。
取5種不同風味劑(草莓、香草、檸檬、葡萄與櫻桃),以0.3%濃度含在美特尼二甲亞碸溶液調配物中,與其對應之安慰劑進行測試,分析其遮蔽效力。其結果示於圖5。並非所有風味劑均使未遮蔽之賽美特尼二甲亞碸溶液之距離縮小。明確言之,調配物4(檸檬香味)與5(葡萄香味)之距離與區分指數均增加,因此其遮蔽溶液味道之效果較低。調配物1(草莓)、2(香草)、與6(櫻桃)之距離數值與區分指數均比未調味之調配物(F0)降低,表示活性溶液之味道已改善。調配物F1、F2與F6之區分指數低於20%,表示這三種調配物遮蔽味道之效果相近。依據此等結果,由風味劑按其遮蔽賽美特尼二甲亞碸溶液味道之效果之排序結果為香草>櫻桃>草莓。草莓風味劑因為香氣高而有附加優勢。味道之人體評估法係利用問卷調查進行相對生體可用率研究,整體反應為該調配物可以接受,而且味道沒有苦味。
一項具體實施例中,提供一種直接粉末掺和調配物,其包含<1.0w/w%(較佳低於0.04% w/w)之微粉化5 N-(3-{3-環丙基-5-[(2-氟-4-碘苯基)胺基]-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基}苯基)乙醯胺二甲亞碸、50.0至80.0w/w%磺基丁基醚β-環糊精(作為溶解劑)、約4.9w/w%檸檬酸與約4.2w/w%磷酸鈉(作為緩衝劑)、5.0至15.0w/w%蔗糖素(作為甜味劑)、0.2至2.0w/w%對羥基苯甲酸甲酯(作為抗微生物防腐劑)、1.0至3.0w/w%山梨酸鉀(作為抗微生物防腐劑)與1.0至5.0w/w%草莓風味劑。
該直接粉末掺和物之組成份可依任何順序組合,其可個別混合或由其中兩種或更多種掺和物組成份預先混合。根據一項具體實施例,組合磺基丁基醚β-環糊精與蔗糖素,先在乾物下預混合,再與其他成份組合。根據一項具體實施例,共同混合所有賦形劑,然後將該預混合物分成兩半,取活性醫藥成份(API)置入其中。
一項具體實施例中,提供一種口服液,其包含5 N-(3-{3-環丙基-5-[(2-氟-4-碘苯基)胺基]-6,8-二甲基-2,4,7-三側氧基
-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基}苯基)乙醯胺二甲亞碸、磺基丁基醚β-環糊精(作為溶解劑)、檸檬酸與磷酸鈉(作為緩衝劑)、對羥基苯甲酸甲酯與山梨酸鉀(作為抗微生物防腐劑)、蔗糖素(作為甜味劑)、草莓風味劑、與水。
一項具體實施例中,提供一種口服液,其包含5N-(3-{3-環丙基-5-[(2-氟-4-碘苯基)胺基]-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基}苯基)乙醯胺二甲亞碸、磺基丁基醚β-環糊精(作為溶解劑)、檸檬酸與磷酸鈉(作為緩衝劑)、羥丙基甲基纖維素(作為溶解劑)與表面活性劑、對羥基苯甲酸甲酯與山梨酸鉀(作為抗微生物防腐劑)、蔗糖素(作為甜味劑)、草莓風味劑、與水。
本發明口服液用粉末(POS)可投與醫療有效量,供治療或預防疾病狀態,例如:說明於上述參考文獻國際申請案案號PCT/JP2005/011082與美國專利公告案案號US 2006/0014768中。
一種抑制人類MEK活性之方法包括對需要處理此等活性之個體投與醫療有效量之本發明直接粉末掺和調配物。
本發明亦提供化合物A之用途,用於製造本發明直接粉末掺和調配物。
本發明亦提供化合物A之用途,用於製造本發明直接粉末掺和調配物,其係用於治療癌症。
本發明亦提供化合物A之用途,用於製造本發明直接粉末掺和調配物,其係用於抑制MEK。
本發明亦提供一種作為MEK抑制劑使用之直接粉末掺和調配物,其包含本發明化合物A與醫藥上可接受之載劑。
本發明亦提供一種用於治療癌症之直接粉末掺和調配物,其包含本發明化合物A與醫藥上可接受之載劑。
本發明亦提供用於抑制MEK之直接粉末掺和調配物,其包含本發明化合物A與醫藥上可接受之載劑。
在未進一步說明下,咸信熟悉此相關技術者可利用上述說明,讓本發明達到最完全利用程度。因此下列實例僅供說明用,
並未限制本發明範圍。
本文採用之所有賦形劑均為標準醫藥級賦形劑,其可自相關技藝上已知之許多製造商取得。
本文所採用代號與其在此等製程、反應圖與實例中慣用法均符合現行科學文獻之用法,例如:the Journal of the American Chemical Society或the Joumal of Biological Chemistry。除非另有說明,否則所有溫度均以℃(攝氏度數)表示。
(i)用於再重組成為調配物之賽美特尼粉末掺和物(實例,批量10,000克)
採用四階段之二次製造程序,讓粉末再重組成溶液調配物,其包括掺合、研磨、掺合與填充。第一個製程步驟為掺合,此製程期間,所有賦形劑均通過20篩目篩網過篩,賽美特尼則通過35篩目篩網過篩,然後移至合適混合器中,如:Servolift 50 L料斗混合機。除了賽美特尼外,取其他所有材料於20 +/- 3rpm下掺合10分鐘。第二個製程步驟為研磨,此單元操作係利用裝配032Cconidur篩板(2A032C02916)之Quadro® Co-mil®在2000rpm下打散結塊與縮小掺和物之粒度分佈。第三步驟中,將打散之材料置回混合機中,於20 +/- 3rpm下掺合10分鐘。隨後,將掺合後之混合物分成兩半,取賽美特尼置入其中,在20 +/- 3rpm下掺合40分鐘,使藥物與賦形劑達到均勻分佈。
實例1之製程產生如下表1所示組成份之組成物。
設計粉末之目標量為13.126克,用於與90mL媒劑(無菌水或純水)再重組成,達到化合物B)終濃度為0.05mg/mL。
調配物製法
表2出示定量上類似實例1之調配物。這兩種調配物均採用相同單元操作與製程參數製造。實例2中改用卡維松替代磺基丁基醚β-環糊精(Captisol)。
實例2製程產生如下表2組成份之調配物。
調配物製法
表3出示定量上類似實例1之調配物。這兩種調配物均採用相同單元操作與製程參數製造。實例3中改用卡維松與羥丙基甲基纖維素(HPMC)替代磺基丁基醚β-環糊精(Captisol)。
實例3製程產生如下表3組成份之調配物。
調配物製法
表4出示定量上類似實例1之調配物。這兩種調配物均採用相同單元操作與製程參數製造。實例4中不使用防腐劑,及改用5克卡維松替代磺基丁基醚β-環糊精(Captisol)。
實例4製程產生如下表4組成份之調配物。
雖然上文說明本發明較佳具體實施例,但咸了解本發明不限於本文揭示之明確之內容說明,並保留屬於申請專利範圍內之所有修飾法之權益。
Claims (13)
- 一種直接粉末掺和調配物,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、與溶解劑;其中,b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;與羥丙基甲基纖維素。
- 根據請求項1之直接粉末掺和調配物,其中該溶解劑為磺基丁基醚β-環糊精。
- 根據請求項1之直接粉末掺和調配物,其中該溶解劑之含量超過約60重量%。
- 一種直接粉末掺和調配物,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、溶解劑、緩衝劑與甜味劑:其中,b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;與羥丙基甲基纖維素;與c)藥物之粒度分佈為至少90%粒子為1至20微米。
- 一種直接粉末掺和調配物,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、溶解劑、緩衝劑與甜味劑:其中, b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;與羥丙基甲基纖維素;與c)藥物之粒度分佈為至少90%粒子為1至20微米。
- 一種口服液,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、溶解劑、防腐劑、緩衝劑、甜味劑、與水性媒劑:其中,b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;或羥丙基甲基纖維素。
- 一種口服液,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醚胺二甲亞碸溶合物)、溶解劑、與水性媒劑:其中,b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;或羥丙基甲基纖維素。
- 一種口服液,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、溶解劑、防腐劑、緩衝劑、甜味劑、風味劑、與水性媒劑:其中, b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;或羥丙基甲基纖維素。
- 一種口服液,其包含:a)一定量之藥物(其係N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲亞碸溶合物)、溶解劑、防腐劑、緩衝劑、甜味劑、表面活性劑、風味劑、與水性媒劑:其中,b)該溶解劑係選自:羥基丙基β-環糊精;磺基丁基醚β-環糊精;羥基丙基β-環糊精與磺基丁基醚β-環糊精之組合;羥基丙基β-環糊精與羥丙基甲基纖維素之組合;磺基丁基醚β-環糊精與羥丙基甲基纖維素之組合;或羥丙基甲基纖維素。
- 根據請求項1至5中任一項之調配物,其係用於治療人類之癌症。
- 根據請求項1至5中任一項之調配物,其係用於抑制人類之MEK。
- 根據請求項6至9中任一項之溶液,其係用於治療人類之癌症。
- 根據請求項6至9中任一項之溶液,其係用於抑制人類之MEK。
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US20200178569A1 (en) * | 2016-04-29 | 2020-06-11 | Alvin Kershman | Method of Coating an Edible Thermoplastic Pet Chew |
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KR102230721B1 (ko) * | 2019-02-01 | 2021-03-22 | 주식회사 오스코텍 | 피리도피리미딘계 염산염을 포함하는 경구용 고형제제 및 이의 제조방법 |
BR112022007603A2 (pt) * | 2019-10-22 | 2022-07-19 | Chemistryrx | Métodos para o tratar hiperplasia epidermica congênita |
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