TW201623323A - 替諾福韋前藥新多晶型及其製備方法和用途 - Google Patents
替諾福韋前藥新多晶型及其製備方法和用途 Download PDFInfo
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Abstract
本發明涉及9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽新晶型及其製備方法和用途。具體地,本發明涉及式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,其特徵在於,該晶型XRPD圖譜中至少包含2θ±0.20°為:5.08,12.44,13.18,22.37,23.37,28.56的衍射峰。本發明晶型具有生物利用度高,藥效顯著,穩定性好,收率高,純度高等特點,有助於藥物给藥途徑的選擇與設計,以及藥物製劑工藝參數的確定,從而提高藥品生產質量。
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Description
本發明涉及醫藥化學領域,具體涉及替諾福韋前藥9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽新晶型及其製備方法,含有治療有效量的該化合物的醫藥組成物及其製藥用途。
9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽(I)。具備如下結構:
9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽(I)是一種核
苷類逆轉錄酶抑制劑,是替諾福韋(PMPA)的前藥。PMPA結構類似天然核苷單磷酸,在體內迅速轉化為活性代謝產物PMPA二磷酸(PMPApp);PMPApp與天然5'三磷酸去氧腺苷競爭,摻入到病毒DNA鏈中,但由於PMPApp缺乏3'OH基團,無法再進行5',3'磷酸二酯鍵偶聯,從而導致DNA鏈延長受阻,最終阻斷病毒的複製(第1圖)。研究證明PMPA具有抗人免疫缺陷病毒(HIV)和乙型肝炎病毒(HBV)活性。
但PMPA含有磷酸基團,在生理pH條件下通常帶負電荷而極性太強不易通過生物膜,導致該類藥物口服生物利用度差、組織分佈係數低,並且具有一定的腎毒性。因此在開發該類藥物時,需要運用前藥原理將磷酸基團的負電荷掩蔽,消除該類藥物的不足。吉利德公司開發的PMPA的雙酯前藥,富馬酸PMPA二吡伏酯(tenofovirdisoproxilfumarate,TDF)分別於2001年被美國食品藥品管理局(FDA)批准用於治療HIV感染。
TDF在一定程度上顯著改善了PMPA的藥物代謝動力學屬性,但它在體內還是很快被血漿中廣泛存在的非特異性酯酶水解,尤其是在腸黏膜上皮細胞碳酸酯酶作用下迅速水解釋放出PMPA。血漿中高濃度PMPA由於其膜透過性差而被迅速排出體外,難以在感染部位保持足夠的濃度;此外,PMPA是腎近端小管上皮細胞有機陰離子轉運體(hOAT)的基質,血漿中高濃度PMPA易在腎近端小管上皮細胞中累積,造成一定的腎毒性風險。
而新一代的單磷醯胺單酯類前藥克服了上述TDF的缺點,在血漿中很穩定,不易被酯酶水解;但被吸收進入細胞內;立即在絲胺酸蛋白酶(cathepsinA)以及體內特異性醯胺酶的作用下轉化為PMPA,因此有更好的組織透過性及淋巴組織和細胞靶向性。吉利德公司開發的單磷醯胺單酯類前藥GS7340(參考專利WO2013052094A2)已經順利進入III期臨床試驗,結果顯示GS7340與30倍劑量的TDF相比,還具有更強的抗病毒能力和更好的安全性。
9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽(I)和GS7340一樣,在細胞內都會釋放出活性成分PMPA。其輔助基團設計巧妙,結構上和GS7340只有一個甲基的區別,輔助基團在細胞內的脫落機制和方式與GS7340基本相同。可以預見,HS-10234由於吸收和分佈上優勢,將比TDF等前藥更為有效地發揮其活性成分PMPA的藥效,作為最有潛力的新一代PMPA前藥造福於廣大患者。
本領域技術人員知道,藥物的多晶型已經成為藥物研究過程和藥品成品品質控制及檢測過程中必不可少的重要組成部分。對藥物多晶型的研究有助於新藥化合物生物活性的選擇,有助於提高生物利用度,增進臨床療效,有助於藥物給藥途徑的選擇與設計,以及藥物製劑工藝參數的確定,從而提高藥品生產品質。同一藥物晶型不同,生物利用度可能差異顯著。同一種藥物,某些晶型可能比其他晶型具備更高的生物活性。獲得一種生物活性更高,更適
合醫藥應用的替諾福韋前藥晶型是醫藥領域一直期待解決的技術問題。
本發明的目的在於解決上述技術問題,提供9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的一種新晶型,本發明將其命名為晶型A。
本發明所述晶型A的XRPD圖譜中至少包含2θ±0.20°為:5.08,12.44,13.18,22.37,23.37,28.56的衍射峰。
較佳的,該9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽晶型A的XRPD圖譜中至少包含2θ±0.20°為:5.08,7.42,10.15,12.44,13.18,22.37,23.37,28.56的衍射峰。更佳的,還包含2θ±0.20°為16.35,18.23,21.36,25.00,31.68的衍射峰。
特別佳的,該晶型A的XRPD圖譜如第1圖所示。
本發明所述的9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽晶型A的差熱分析結果表明,在110.9℃出現一個尖銳的吸熱熔融峰。
本發明的另一目的在於提供9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的晶型A的製備方法,包括如下步驟:①將任意形態的9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)
-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽在有機溶劑中加熱溶解;②將9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的溶解液冷却析晶;③過濾晶體得到晶型A。
較佳的,該有機溶劑选自乙腈、無水甲醇、無水乙醇、異丙醇、無水甲醇/正庚烷、無水乙醇/正庚烷、異丙醇/正庚烷、無水甲醇/甲基第三丁基醚、無水乙醇/甲基第三丁基醚、異丙醇/甲基第三丁基醚、無水甲醇/異丙醚、無水乙醇/異丙醚、異丙醇/異丙醚、無水甲醇/乙醚、無水乙醇/乙醚或異丙醇/乙醚,其中較佳為無水甲醇/正庚烷。
較佳的,有機溶劑加熱溶解溫度一般為30℃至回流溫度,較佳為回流溫度;析晶溫度較佳為-40~40℃,最佳為0℃~10℃。
本發明的另一目的還在於提供一種包含有效量的該晶型A的醫藥組成物,任選的,該組成物中還包含藥學上可接受的載體。
本發明的组合物包括適於口服和注射等給藥途徑,較佳為口服給藥藥途徑。劑型包括片劑,膠囊,分散劑和混懸劑,較佳為片劑。
本發明的另一目的還在於提供該晶型A及含有晶型A的醫藥組成物在在製備治療愛滋病或乙型病毒性肝炎藥物中的應用。
本發明的新晶型A具有生物利用度高,藥效顯著,穩定性好,收率高,純度高等特點。本發明的新晶型有助於藥物給藥途徑的選擇與設計,以及藥物製劑工藝參數的確定,從而提高藥品生產品質。
第1圖是本發明9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽新晶型的XRPD圖譜。
第2圖是本發明9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽新晶型的DSC圖譜。
為體現本發明的技術方案及其所取得的效果,下面將結合具體實施例對本發明做進一步說明,但本發明的保護範圍並非侷限於具體實施例。
將9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽5.0g,無水甲醇20.0ml和正庚烷5ml置於反應瓶中,加熱至回流,使固體完全溶解,關閉加熱,降溫至0~10℃攪拌析晶2h,過濾固體得到晶型A。
經檢測驗證,其X射線粉末衍射圖譜如第1圖所示,其DSC圖譜與第2圖吻合,證明了所得晶型為晶型A。
將9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽5.0g,無水乙醇20.0ml置於反應瓶中,加熱至回流,使固體完全溶解,關閉加熱,降溫至0~10℃攪拌析晶2h,過濾固體得到晶型A。
經檢測驗證,其X射線粉末衍射圖譜與第1圖吻合,其DSC圖譜與第2圖吻合,證明了所得晶型為晶型A。
將9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽5.0g,異丙醇20.0ml和甲基第三丁基醚5ml置於反應瓶中,加熱至回流,使固體完全溶解,關閉加熱,降溫至0~10℃攪拌析晶2h,過濾固體得到晶型A。
經檢測驗證,其X射線粉末衍射圖譜與第1圖吻合,其DSC圖譜與第2圖吻合,證明了所得晶型為晶型A。
對本發明實施例一的方法製備的新晶型進行穩定性考察,結果表明,本發明的新晶型晶型A在穩定性試驗中沒有發生轉晶,同時也沒有發生化學降解,在室溫下是穩定的,符合藥物及製劑需求,詳見下表:
。
對本發明實施例一、二、三製備的新晶型進行流動性考察,結果表明,本發明的新晶型晶型A流動性良好。
對本發明製備的新晶型晶型A,藉由大鼠靜脈注射給藥和口服給藥測定的絕對生物利用度高達81%。實驗表明本發明製備的新晶型具有較高的生物利用度。
Claims (19)
- 一種式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,
- 如申請專利範圍第1項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,其中,該晶型的XRPD圖譜中至少包含2θ±0.20°為:5.08,7.42,10.15,12.44,13.18,22.37,23.37,28.56的衍射峰。
- 如申請專利範圍第2項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,其中,該晶型的XRPD圖譜中進一步還包含16.35,18.23,21.36,25.00,31.68的衍射峰。
- 如申請專利範圍第1項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基] 甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,其中,該晶型的差熱分析結果表明,在110.9℃出現一個尖銳的吸熱熔融峰。
- 如申請專利範圍第1至3項中任一項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,其中該晶體具有與第1圖基本一致的X射線衍射圖。
- 一種申請專利範圍第1至3項中任一項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型的製備方法,包括如下步驟:1)將任意形態的9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽在有機溶劑中加熱溶解;2)將9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的溶解液冷却析晶;3)過濾晶體得到目標晶型。
- 如申請專利範圍第6項所述的製備方法,其中,該有機溶劑選自乙腈、無水甲醇、無水乙醇、異丙醇、無水甲醇/正庚烷、無水乙醇/正庚烷、異丙醇/正庚烷、無水甲醇/甲基第三丁基醚、無水乙醇/甲基第三丁基醚、異丙醇/甲基第三丁基醚、無水甲醇/異丙醚、無水 乙醇/異丙醚、異丙醇/異丙醚、無水甲醇/乙醚、無水乙醇/乙醚或異丙醇/乙醚。
- 如申請專利範圍第7項所述的製備方法,其中,該有機溶劑為無水甲醇/正庚烷。
- 如申請專利範圍第6項所述的製備方法,其中,有機溶劑加熱溶解溫度一般為30℃至回流溫度。
- 如申請專利範圍第9項所述的製備方法,其中,有機溶劑加熱溶解溫度一般為回流溫度。
- 如申請專利範圍第6項所述的製備方法,其中,冷卻析晶溫度為-40~40℃。
- 如申請專利範圍第11項所述的製備方法,其中,冷卻析晶溫度為0~10℃。
- 一種醫藥組成物,其包含如申請專利範圍第1至4項中任一項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型,任選的,還包含藥學可接受的載體。
- 如申請專利範圍第13項所述的醫藥組成物,其中,該組成物適於口服和注射等給藥途徑。
- 如申請專利範圍第14項所述的醫藥組成物,其中,該組成物適於口服给藥途徑。
- 如申請專利範圍第13項所述的醫藥組成物,其中,該組成物可以製成片劑,膠囊,分散劑和混懸劑。
- 如申請專利範圍第16項所述的醫藥組成物,其中,該 組成物可以製成片劑。
- 一種申請專利範圍第1至4項中任一項所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(異丙氧基羰基)-1-甲基]乙基]胺基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富馬酸鹽的新晶型的用途,其用於製備治療或預防愛滋病或乙型病毒性肝炎藥物。
- 一種申請專利範圍第9至11項中任一項所述的醫藥組成物的用途,其用於製備治療或預防愛滋病或乙型病毒性肝炎藥物。
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