TWI822779B - 包含第三代小分子egfr抑制劑的醫藥組成物及其製備方法 - Google Patents
包含第三代小分子egfr抑制劑的醫藥組成物及其製備方法 Download PDFInfo
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Abstract
本發明涉及包含第三代小分子EGFR抑制劑的醫藥組成物及其製備方法,該組合物具有良好的穩定性和藥物溶出度,產品質量可控,製備方法工藝簡單、可操作性強、重現性良好、適宜大規模工業化生產。
Description
本發明屬於藥物製劑領域,具體涉及一種包含第三代小分子EGFR抑制劑的醫藥組成物及其製備方法。
EGFR(Epidermal Growth Factor Receptor)是跨膜蛋白酪胺酸激酶erbB受體家族的一員。藉由與其配體-例如表皮生長因子(EGF)的結合,EGFR在細胞膜上可以形成同源二聚體,或者與家族中其他的受體(比如erbB2,erbB3,或erbB4)形成異源二聚體。這些二聚體的形成,可引起EGFR細胞內關鍵的酪胺酸殘基磷酸化,從而激活細胞內多個下游的信號通路。這些細胞內信號通路在細胞增殖、生存及抗凋亡中起重要作用。EGFR信號傳導通路失調,包括配體及受體的表達增高、EGFR基因擴增以及突變等,可促進細胞向惡性轉化,並在腫瘤細胞的增殖、侵襲、轉
移以及血管形成中發揮重要作用。因此,EGFR是抗癌藥物開發的合理靶點。
本發明提供一種包含第三代小分子EGFR化合物的醫藥組成物。
該醫藥組成物包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽、其多晶型物、溶劑合物、水合物、藥學上可接受的鹽或它們的組合作為活性成分,以及至少一種藥學上可接受的輔料。
根據本發明的醫藥組成物,所述活性成分的含量為1-60%。
根據本發明的醫藥組成物,所述活性成分的單位劑量為10-200mg,較佳55-110mg,更佳55mg或110mg。
根據本發明的醫藥組成物,所述輔料包括一種或多種填充劑,至少包含一種二糖或多糖,例如葡聚糖、澱粉、纖維素、乳糖、麥芽糖或蔗糖。澱粉可選自馬鈴薯澱粉、玉米澱粉、米澱粉、小麥澱粉支鏈澱粉或預膠化澱粉等,其中,所述二糖或多糖的含量為1-60%,較佳5-55%,更佳5-30%,進一步較佳5-15%。
較佳填充劑為二糖,例如乳糖,其含量為為1-60%,較佳5-55%,更佳5-30%,進一步較佳5-15%。
根據本發明的醫藥組成物,所述輔料包括一種或多種填充劑、崩解劑或潤滑劑。
根據本發明的醫藥組成物,所述填充劑包括微晶纖維素、乳糖、無水乳糖、玉米澱粉、預膠化澱粉、甘露醇、山梨醇、磷酸氫鈣、硫酸鈣中的一種或多種,其中所述填充劑的含量為20-80%,較佳30-50%。較佳的,選自上述組分的兩種,並且兩種組分的重量比為1:3-3:1。
根據本發明的醫藥組成物,較佳微晶纖維素和乳糖。以片芯重量計,所述微晶纖維素的含量為1-60%,較佳10-40%,更佳20-40%;乳糖的含量為1-60%,較佳5-30%,更佳5-15%。可選擇的技術方案方案包括但不限於,微晶纖維素1-60%,乳糖的含量為1-60%;微晶纖維素10-40%,乳糖的含量為5-30%;微晶纖維素20-40%,乳糖的含量為5-15%。
進一步較佳地,微晶纖維素與乳糖的重量比為1:3-3:1,更較佳2-3:1。
進一步較佳地,乳糖為無水乳糖。以片芯重量計,所述微晶纖維素的含量為1-60%,較佳10-40%,更佳20-40%;無水乳糖的含量為1-60%,較佳5-30%,更佳5-15%。可選擇的技術方案方案包括但不限於,微晶纖維素1-60%,無水乳糖的含量為1-60%;微晶纖維素10-40%,無水乳糖的含量為5-30%;微晶纖維素20-40%,無水乳糖的含量為5-15%。
進一步較佳地,微晶纖維素與無水乳糖的重量比為1:3-3:1,更佳2-3:1。
藉由乳糖的加入,可製備得到高含量的式I化合物的醫藥組成物,載藥量可達40%以上,同時得到的醫藥組成物可壓性好,溶出一致。
根據本發明的醫藥組成物,所述崩解劑包括低取代羥丙基纖維素、交聯羧甲基纖維素鈉、羧甲澱粉鈉、交聯聚維酮中的一種或多種,較佳羧甲澱粉鈉。其中崩解劑的含量為1-30%,較佳10-20%。所述崩解劑
以全內加的方式能夠保證片劑良好的崩解和製備。藉由加入羧甲澱粉鈉,可以進一步提高製劑的穩定性。較佳地,所述崩解劑藉由內加方式加入。
根據本發明的醫藥組成物,所述潤滑劑包括滑石粉、硬脂酸、硬脂富馬酸鈉、山崳酸甘油酯、硬脂酸鎂、微粉矽膠中的一種或多種。以片芯重量計,其中所述潤滑劑的含量為0.1-10%,較佳0.2-5%。
進一步的,較佳硬脂富馬酸鈉和硬脂酸鎂,硬脂富馬酸鈉的含量為0.1-5%,較佳0.3-3%,硬脂酸鎂的含量為0.1-5%,較佳0.2-2%;硬脂富馬酸鈉和硬脂酸鎂聯用能夠明顯改善原料在設備表面的吸附,保證製備過程的順利,使製劑成品保持優良的溶出效果。
根據本發明的醫藥組成物,所述含量是指占藥物總重量的百分比,所述藥物總重量不包括包衣的重量,對於具體劑型而言,如占片芯或顆粒的重量。
本發明的醫藥組成物為口服製劑,選自片劑或膠囊劑,較佳薄膜劑,更佳速釋薄膜衣片,包衣劑為胃溶型薄膜包衣預混劑,較佳歐巴代85F140124(主要成分為聚乙烯醇,聚乙二醇,滑石粉,二氧化鈦,氧化鐵紅,氧化鐵黑)、歐巴代85F12300(主要成分為聚乙烯醇,聚乙二醇,滑石粉,二氧化鈦,氧化鐵黃)。
本發明進一步還提供一種醫藥組成物的製備方法,主要包括以下步驟:1)原輔料預處理:將填充劑、崩解劑、潤滑劑過篩備用;2)混合:按量稱量各內加原輔料並混合;3)乾法製粒:將上述混合後的粉末以乾法製粒;4)總混:將製得的顆粒以及外加潤滑劑混合;
5)視需要地,壓片:按理論片重壓製成片;6)視需要地,包衣。上述製備方法的具體步驟包括:1)原輔料預處理:將微晶纖維素、無水乳糖過60目篩,硬脂富馬酸鈉、羧甲澱粉鈉過80目篩,備用;2)混合:按處方量稱量各內加原輔料,將微晶纖維素、無水乳糖、羧甲澱粉鈉、硬脂富馬酸鈉、活性成分、硬脂酸鎂加入到料斗混合機內進行混合;3)乾法治粒:將上述混合後的粉末以乾法制粒機進行製顆粒;4)總混:將製得的顆粒細粉以及外加的處方量硬脂富馬酸鈉加入到料斗混合機內進行混合;5)視需要地,壓片:按理論片重,壓製成片;6)視需要地,包衣:i)配製包衣液,向純化水中邊攪拌邊加入處方量的歐巴代配成固含量為10%的包衣液,待其完全加入後攪拌60min使其分散均勻,將配製好的包衣液過100目篩網,備用;ii)根據工藝要求設定參數,待包衣增重達約2.0%~4.0%時結束包衣。
發明人藉由大量的研究發現,N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺作為第三代小分子EGFR化合物,其溶解度受pH影響較大,具有pH依賴性,為低滲透性藥物。而本發明製備的醫藥組成物,在不同的溶出介質下均有很好的溶出,並且溶出一致。
關於填充劑:
藉由表1可以發現,當填充劑包含乳糖時,可製備得到高含量的式I化合物的醫藥組成物,同時得到的醫藥組成物可壓性好。
進一步提高片劑中活性成分的載藥量,當活性成分的含量為43.3%時,片劑仍具有非常好的可壓性,製備得到的素片光潔,無黏沖現象,已製備片劑形狀完整、外觀良好,合格率為100%。
此外,裸片的硬度也是影響溶出度的因素之一,硬度不均可能導致溶出不均勻進而影響藥效,下表3給出了本發明處方在不同硬度時對應的溶出度情況,對比表中內容可知,本發明處方在不同裸片硬度條件下能夠消除裸片硬度變化對溶出結果的影響,使產品保持良好的溶出度,因此,本發明處方可以解決不同裸片硬度帶來的不利影響。
關於崩解劑:
在本發明醫藥組成物體系中,崩解劑的添加同樣會影響片劑的溶出度,發明人發現,崩解劑的用量在1-30%的範圍內時溶出度優良,具體參見表4,當選擇羧甲澱粉鈉作為崩解劑時,能夠保證片劑良好的崩解和製備,較佳的用量為10%~20%。
實施例1
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含64.9mg的活性成分(以C30H35N7O2‧CH3SO3H計),45.0mg的微晶纖維素(KG802),15.3mg的無水乳糖
(21AN),21.0mg的羧甲澱粉鈉(A型),0.8mg內加的硬脂富馬酸鈉,1.5mg外加的硬脂富馬酸鈉,1.5mg的硬脂酸鎂,處方如下:
包含上述組分的速釋薄膜衣片,利用下述製備方法製備:
(1)輔料預處理
(2)稱量
按配料核料單量稱取原輔料。
(3)混合
1)預混I:內加原輔料於料斗混合機中進行混合,轉速:15rpm、時間:10min;2)整粒:篩網孔徑:1.0mm、整粒速度:350~800rpm;3)
預混II:將整粒後物料與硬脂酸鎂投入料斗混合機中進行混合,轉速:15rpm、時間:10min。
(4)乾法製粒
送料變頻(Hz):7~13;壓片變頻(Hz):20~40;製粒變頻(Hz):30~50;製粒篩網孔徑:1.0mm;細粉目數:60目。
(5)總混
將乾法治粒所得顆粒細粉及外加的處方量硬脂富馬酸鈉投入料斗混合機,設定運行速度15rpm,混合10min。
(6)壓片:
根據顆粒含量計算應壓片重,調整片重、硬度合格後正式壓片。
(7)包衣
①包衣液的配製:將薄膜包衣預混劑(胃溶型)用處方量的純化水配成固含量為10%的包衣液。攪拌60min後,用100目篩濾過,備用;②包衣:根據工藝要求設定相關參數,包衣過程中控制片床溫度30~40℃,包衣增重為2.0~4.0%。
(8)包裝。
實施例2
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含129.8mg的活性成分(以C30H35N7O2‧CH3SO3H計),90.0mg的微晶纖維素(KG802),30.6mg的無水乳糖(21AN),42.0mg的羧甲澱粉鈉(A型),1.6mg內加的硬脂富馬酸鈉,3.0mg外加的硬脂富馬酸鈉,3.0mg的硬脂酸鎂。處方如下:
包含上述組分的速釋薄膜衣片,利用下述製備方法製備:
(1)輔料預處理
(2)稱量
按配料核料單量稱取原輔料。
(3)混合
1)預混I:內加原輔料(微晶纖維素(KG802)、無水乳糖(21AN)、羧甲澱粉鈉(A型)、硬脂富馬酸鈉、原料藥)於料斗混合機中進行混合,轉速:15rpm、時間:20min;2)預混II:向預混I結束後的料斗中加入硬脂酸鎂(內)進行混合,轉速:15rpm、時間10min。
(4)乾法製粒
HFS轉速:30~45rpm、VFS轉速:200~240rpm、壓輪轉速:3~7rpm、壓輪壓力:20~25KN、粉碎刀轉速:1000~1500rpm、壓輪間隙:1.0mm、製粒篩網孔徑:1.6mm。
(5)總混
將乾法製粒所得顆粒細粉及外加的處方量硬脂富馬酸鈉投入料斗混合機,設定運行速度15rpm,混合10min。
(6)壓片:
根據顆粒含量計算應壓片重,調整片重、硬度合格後正式壓片。
(7)包衣
①包衣液的配製:將薄膜包衣預混劑(胃溶型)用處方量的純化水配成固含量為10%的包衣液。攪拌60min後,用80目篩濾過,備用;②包衣:根據工藝要求設定相關參數,包衣過程中控制片床溫度30~40℃,包衣增重為2.0~4.0%。
(8)包裝。
實施例3
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含5.9mg的活性成分(以C30H35N7O2‧CH3SO3H計),25.0mg的微晶纖維素,54.7mg的無水乳糖,15.0mg的羧甲澱粉鈉,0.5mg內加的硬脂富馬酸鈉,0.9mg外加的硬脂富馬酸鈉,0.5mg的硬脂酸鎂。處方如下:
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
實施例4
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含31.8mg的活性成分(以C30H35N7O2‧CH3SO3H計),30.0mg的微晶纖維素,89.4mg的無水乳糖,30.0mg的羧甲澱粉鈉,1.0mg內加的硬脂富馬酸鈉,1.8mg外加的硬脂富馬酸鈉,1.0mg的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例2。
實施例5
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含47.2mg的活性成分(以C30H35N7O2‧CH3SO3H計),30.0mg的微晶纖維素,93mg的無水乳糖,30.0mg的羧甲澱粉鈉,1.0mg內加的硬脂富馬酸鈉,1.8mg外加的硬脂富馬酸鈉,2.0mg的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
實施例6
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含97.35g的活性成分(以C30H35N7O2‧CH3SO3H計),67.5g的微晶纖維素,22.95g的無水乳糖,31.5g的羧甲澱粉鈉,1.2g內加的硬脂富馬酸鈉,2.25g外加的硬脂富馬酸鈉,2.25g的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例2。
實施例7
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含259.6g的活性成分(以C30H35N7O2‧CH3SO3H計),180.0g的微晶纖維素,61.2g的無水乳糖,84.0g的羧甲澱粉鈉,3.2g內加的硬脂富馬酸鈉,6.0g外加的硬脂富馬酸鈉,6.0g的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
實施例8
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含97.35g的活性成分(以C30H35N7O2‧CH3SO3H計),67.5g的微晶纖維素,22.95g的無水乳糖,31.5g的羧甲澱粉鈉,1.2g內加的硬脂富馬酸鈉,2.25g外加的硬脂富馬酸鈉,2.25g的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例2。
實施例9
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含47.2mg的活性成分(以C30H35N7O2‧CH3SO3H計),30.0mg的山梨醇,93mg的磷酸氫鈣,30.0mg的交聯聚維酮XL,1.0mg內加的硬脂富馬酸鈉,1.8mg外加的硬脂酸,2.0mg的滑石粉。
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
實施例10
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含47.2mg的活性成分(以C30H35N7O2‧CH3SO3H計),30.0mg的蔗糖,93mg的磷酸氫鈣,30.0mg的交聯聚維酮XL,1.0mg內加的硬脂富馬酸鈉,1.8mg外加的硬脂酸,2.0mg的滑石粉。
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
實施例11
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含97.35g的活性成分(以C30H35N7O2‧CH3SO3H計),67.5g的微晶纖維素,22.95g的麥芽糖,31.5g的羧甲澱粉鈉,1.2g內加的硬脂富馬酸鈉,2.25g外加的硬脂富馬酸鈉,2.25g的硬脂酸鎂。
包含上述組分的速釋薄膜衣片,製備方法同實施例2。
實施例12
一種包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽的醫藥組成物,其藥物組成為,包含64.9mg的活性成分(以C30H35N7O2‧CH3SO3H計),45.0mg的微晶纖維素(KG802),15.3mg的玉米澱粉,21.0mg的羧甲澱粉鈉(A型),0.8mg內加的硬脂富馬酸鈉,1.5mg外加的硬脂富馬酸鈉,1.5mg的硬脂酸鎂,處方如下:
包含上述組分的速釋薄膜衣片,製備方法同實施例1。
穩定性檢測及結果分析
1.產品在不同溶出介質中的穩定性
色譜條件:
儀器與試劑 高效液相色譜儀、電子分析天平、磷酸二氫鉀(色譜純)、乙腈(色譜純)、有關物質系統適用性對照品
色譜條件 十八烷基矽烷鍵合矽膠為填充劑(Waters XBridge C18,4.6mm×150mm,3.5μm或效能相當的色譜管柱);流速:1.0ml/min;檢測波長為220nm;管柱溫為35℃;進樣體積:10μl。
流動相A 取2.72g磷酸二氫鉀,加水約900ml溶解後,用氫氧化鈉溶液調節pH值至6.0,再加水至1000ml,混合均勻,過濾,脫氣
流動相B 乙腈
按下表進行梯度洗脫(流動相量可縮放)
0.05%磷酸溶液 取磷酸0.5ml至1000ml水中,混合均勻。
稀釋液 0.05%磷酸溶液800ml與乙腈200ml,混合均勻。
發明人以實施例1製備的片劑為例,研究了其在0.1mol/L鹽酸溶液、pH4.5醋酸鹽緩衝液、pH6.8磷酸鹽緩衝液、pH6.8磷酸鹽緩衝
液(含0.1%SDS)、水和水(含0.1%SDS)中的溶液穩定性。參照溶出度與釋放度測定法(中國藥典2015年版四部通則0931第二法),50rpm的條件下,經30min時取溶出液過濾,取續濾液作為供試品溶液,考察室溫下24h內的溶液穩定性。溶液穩定性數據詳見表4。
結果表明,本發明製備的片劑在0.1mol/L鹽酸溶液、pH4.5醋酸鹽緩衝液、pH6.8磷酸鹽緩衝液(含0.1%SDS)、水和水(含0.1%SDS)中24小時內均穩定;在pH6.8磷酸鹽緩衝液中略有降解。
2.光照、高溫、高濕條件下的穩定性
參見表6-8,影響因素試驗考察30天(光照條件下考察至10天,光照總照度不低於1.2×106lux.hr),結果表明,本品在光照(總照度1.2×106lux/hr)條件下樣品穩定,不降解,各項質量指標沒有明顯變化;在高溫(40℃)、高溫(60℃)、25℃/RH75%條件下,有關物質略有降解,其餘各項質量指標沒有明顯變化,樣品穩定性良好。
3.產品穩定性
結合表9-10的內容可知,本發明所製備片劑質量優良,穩定性考察過程中產品質量穩定,本品處方及工藝穩定,重現性良好。
其餘實施例製備的樣品均具有與實施例1和2類似的穩定性效果。
溶出檢測及結果分析
1.隨機抽取實施例1製備的產品中的四個批次進行檢測,結果如表10所示。
結果表明,生產的樣品均具有良好的溶出均一性。
2.對實施例2製取的產品進行不同介質的溶出檢測,結果如表12所示。
結果表明,本發明製備的產品在不同介質中均具有良好的溶出度。
其餘實施例製備的樣品具有與實施例1和2類似的溶出特性。
Claims (42)
- 一種醫藥組成物,包含N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺,其異構體、溶劑合物、水合物,或其藥學上可接受的鹽,或它們的組合作為活性成分,以及至少一種藥學上可接受的輔料,該輔料包括一種或多種填充劑,該填充劑選自微晶纖維素和乳糖,且該微晶纖維素與乳糖的重量比為1:3-3:1。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該活性成分為N-(5-((4-(1-環丙基-1H-吲哚-3-基)嘧啶-2-基)胺基)-2-((2-(二甲胺基)乙基)(甲基)胺基)-4-甲氧苯基)丙烯醯胺甲磺酸鹽。
- 如申請專利範圍第1或2項所述的醫藥組成物,其中,該活性成分的含量為1-60%。
- 如申請專利範圍第1或2項所述的醫藥組成物,其中,該活性成分的含量為35-50%。
- 如申請專利範圍第3項所述的醫藥組成物,其中,該活性成分的單位劑量為10-200mg。
- 如申請專利範圍5項所述的醫藥組成物,其中,該活性成分的單位劑量為55-110mg。
- 如申請專利範圍第6項所述的醫藥組成物,其中,該活性成分的單位劑量為55mg和110mg。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該微晶纖維素的含量為1-60%;該乳糖的含量為1-60%。
- 如申請專利範圍第8項所述的醫藥組成物,其中,該微晶纖維素的含量為10-40%;該乳糖的含量為5-30%。
- 如申請專利範圍第9項所述的醫藥組成物,其中,該微晶纖維素的含量為20-40%;該乳糖的含量為5-15%。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該微晶纖維素與乳糖的重量比為2-3:1。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該填充劑選自微晶纖維素和無水乳糖。
- 如申請專利範圍第12項所述的醫藥組成物,其中,該微晶纖維素的含量為1-60%;該無水乳糖的含量為1-60%。
- 如申請專利範圍第13項所述的醫藥組成物,其中,該微晶纖維素的含量為10-40%;該無水乳糖的含量為5-30%。
- 如申請專利範圍第14項所述的醫藥組成物,其中,該微晶纖維素的含量為20-40%;該無水乳糖的含量為5-15%。
- 如申請專利範圍第12項所述的醫藥組成物,其中,該微晶纖維素與無水乳糖的重量比為1:3-3:1。
- 如申請專利範圍第16項所述的醫藥組成物,其中,該微晶纖維素與無水乳糖的重量比為2-3:1。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該填充劑的含量為20-80%。
- 如申請專利範圍第1項所述的醫藥組成物,其中,該填充劑的含量為30-50%。
- 如申請專利範圍第1或2項所述的醫藥組成物,其中,該輔料包括一種或多種崩解劑。
- 如申請專利範圍第20項所述的醫藥組成物,其中,該崩解劑選自低取代羥丙基纖維素、交聯羧甲基纖維素鈉、羧甲澱粉鈉或交聯聚維酮中的一種或多種。
- 如申請專利範圍第21項所述的醫藥組成物,其中,該崩解劑選自羧甲澱粉鈉。
- 如申請專利範圍第20項所述的醫藥組成物,其中,該崩解劑的含量為1-30%。
- 如申請專利範圍第23項所述的醫藥組成物,其中,該崩解劑的含量為10-20%。
- 如申請專利範圍第20項所述的醫藥組成物,其中,該崩解劑藉由內加方式加入。
- 如申請專利範圍第1或2項所述的醫藥組成物,其中,該輔料包括一種或多種潤滑劑。
- 如申請專利範圍第26項所述的醫藥組成物,其中,該潤滑劑選自滑石粉、硬脂酸、硬脂富馬酸鈉、山崳酸甘油酯、硬脂酸鎂或微粉硅膠中的一種或多種。
- 如申請專利範圍第27項所述的醫藥組成物,其中,該潤滑劑選自硬脂富馬酸鈉和硬脂酸鎂。
- 如申請專利範圍第26項所述的醫藥組成物,其中,該潤滑劑的含量為0.1-10%。
- 如申請專利範圍第26項所述的醫藥組成物,其中,該潤滑劑的含量為0.2-5%。
- 如申請專利範圍第26項所述的醫藥組成物,其中,該潤滑劑選自硬脂富馬酸鈉和硬脂酸鎂。
- 如申請專利範圍第31項所述的醫藥組成物,其中,該硬脂富馬酸鈉的含量為0.1-5%,該硬脂酸鎂的含量為0.1-5%。
- 如申請專利範圍第32項所述的醫藥組成物,其中,該硬脂富馬酸鈉的含量為0.3-3%,該硬脂酸鎂的含量為0.2-2%。
- 如申請專利範圍第1或2項所述的醫藥組成物,其中,該醫藥組成物為口服製劑。
- 如申請專利範圍第36項所述的醫藥組成物,其中,該醫藥組成物為片劑或膠囊劑。
- 如申請專利範圍第37項所述的醫藥組成物,其中,該醫藥組成物為包衣片劑。
- 如申請專利範圍第38項所述的醫藥組成物,其中,該醫藥組成物為速釋薄膜衣片。
- 如申請專利範圍第39項所述的醫藥組成物,其中,該速釋薄膜衣片的包衣劑為胃溶型薄膜包衣預混劑。
- 一種如申請專利範圍第1至40項中任一項所述的醫藥組成物的製備方法,其特徵在於,包括以下步驟:1)原輔料預處理:將填充劑、崩解劑、內加潤滑劑過篩備用;2)混合:按量稱量各內加原輔料並混合;3)乾法製粒:將上述混合後的粉末以乾法製粒;4)總混:將製得的顆粒以及外加潤滑劑混合;5)視需要地,壓片;6)視需要地,包衣;其中,該填充劑選自微晶纖維素和乳糖,且該微晶纖維素與乳糖的重量比為1:3-3:1。
- 如申請專利範圍第41項所述的製備方法,具體步驟包括:1)原輔料預處理:將微晶纖維素、乳糖、硬脂富馬酸鈉、羧甲澱粉鈉過篩,備用;2)混合:按處方量稱量各內加原輔料,將微晶纖維素、乳糖、羧甲澱粉鈉、硬脂富馬酸鈉、活性成分、硬脂酸鎂加入到料斗混合機內進行混合;3)乾法製粒:將上述混合後的粉末以乾法製粒機進行製顆粒; 4)總混:將製得的顆粒細粉以及外加的處方量硬脂富馬酸鈉加入到料斗混合機內進行混合;5)視需要地,壓片;6)視需要地,包衣:i)配製包衣液,向純化水中邊攪拌邊加入處方量的歐巴代配成固含量為10%的包衣液,攪拌均勻、過篩,備用;ii)待包衣增重達約2.0%~4.0%時結束包衣。
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