TWI704918B - 含有細胞周期蛋白抑制劑的藥物製劑及其製備方法 - Google Patents
含有細胞周期蛋白抑制劑的藥物製劑及其製備方法 Download PDFInfo
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- TWI704918B TWI704918B TW104136656A TW104136656A TWI704918B TW I704918 B TWI704918 B TW I704918B TW 104136656 A TW104136656 A TW 104136656A TW 104136656 A TW104136656 A TW 104136656A TW I704918 B TWI704918 B TW I704918B
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
本發明屬於藥物製劑領域,具體涉及用於細胞周期蛋白抑制劑的藥物製劑及其製備方法。
細胞周期蛋白依賴性激酶(CDK)共有13個成員,都屬絲胺酸/蘇胺酸蛋白激酶家族,依賴與細胞周期蛋白(cyclin)的結合,促進細胞周期時相轉變,啟動DNA合成以及調控細胞轉錄等關鍵功能。
CDKs在所有細胞包括健康和腫瘤細胞的增殖與死亡中所起的關鍵作用,廣泛的CDK抑制劑,尤其是針對未經過基因篩選的患者很難展現較高的治療窗口。劑量大了毒性太高,而小了又沒有藥效。所以選擇性地抑制部分CDK就變得格外重要。當然因為大部分CDK亞型具有相對近似的化學結構,如何提高CDK抑制劑的選擇性又是另外一個挑戰。
CDK4/6作為抗腫瘤標靶的優勢在於:①CDK4/6的抑制劑不表現出“泛-CDK抑制劑”的細胞毒
性,如骨髓抑制和腸道反應;②細胞cyclin D水準升高或者P161NK4a失活,能夠增加細胞對藥物的敏感性,腫瘤細胞相對於正常細胞存在上述現象,所以一定程度上增加了藥物的靶向性。
式I化合物是一種靶向性CDK4/6抑制劑,能夠選擇性抑制細胞周期蛋白依賴性激酶4和6(CDK4/6),恢復細胞周期控制,阻斷腫瘤細胞增殖。其作用於MDA-MB-435乳腺癌細胞,能有效降低Rb在Ser780和Ser795位點磷酸化,IC50分別為66nM和63nM。
乳腺癌是女性最常見的惡性腫瘤之一,具有發病率高,頗具侵襲性,但病程進展緩慢。據國際癌症研究中心公佈的資料顯示,2012年全球約有167萬新發病例,占所有癌症的25%。美國國家癌症中心流行病學調查和最終結果(SEER)統計,2013年美國估計性乳腺癌發病率為123.8/10萬人,2005至2009年亞裔人群女性乳腺癌發病率為94.5/10萬人;我國無官方資料,據估計我國有60%至70%的乳腺癌患者雌激素或孕激素受體呈陽性,推算我國雌激素受體陽性乳腺癌2005至2009年發病率為56.7至66.15/10萬人。Thomson預測,本品上市後銷售額將大幅上升,2019年銷售額將達20.27億美元。
本發明的技術方案是藉由下列方式實現的:
藥物組合物,其包括式I化合物或其鹽,以及藥學上可接受的賦形劑作為載體,該等鹽型包括鹽酸鹽、羥乙基磺酸鹽。
較佳的,式I化合物占該等組合物重量的10%至80%,較佳係15至60%,進一步較佳係20至40%。
任選的,該等組合物中還可以包含矯味劑、著色劑或包衣材料,最佳的,上述各組分的重量百分比之和為100%。
任選的,該等組合物中還可以包含矯味劑、著色劑或包衣材料,最佳的,上述各組分的重量百分比之和為100%。
較佳的,該等稀釋劑選自澱粉、糖粉、糊精、乳糖、預膠化澱粉、磷酸氫鈣、硫酸鈣、碳酸鈣、甘露醇、山梨醇、微晶纖維素的至少一種,進一步較佳的,該等稀釋劑選自乳糖、微晶纖維素、澱粉或甘露醇中的至少一種,更佳的,該等稀釋劑選自乳糖和微晶纖維素。
較佳的,該等乳糖和微晶纖維素的重量比為1:2至2:1,較佳係1:1。
較佳的,該等黏合劑選自澱粉漿、羥丙甲纖維素、羥丙纖維素、聚維酮、甲基纖維素、羧甲基纖維素鈉、聚乙二醇的至少一種,更佳的,該等稀釋劑選自羥
丙基纖維素或聚維酮的至少一種。
較佳的,該等崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉、交聯聚維酮、乾澱粉、低取代羥丙基纖維素的至少一種,更佳的,該等崩解劑選自交聯聚維酮、羧甲澱粉鈉、交聯羧甲基纖維素鈉中的至少一種。
較佳的,該等潤滑劑選自硬脂酸鎂、硬脂酸、硬脂富馬酸鈉、山崳酸甘油酯、膠態二氧化矽、滑石粉、二氧化矽中的至少一種,更佳的,該等潤滑劑選自硬脂酸、山崳酸甘油酯、膠態二氧化矽中的至少一種。
較佳的,該等表面活性劑為十二烷基硫酸鈉、吐溫80和泊洛沙姆,更佳的,該等表面活性劑為十二烷基硫酸鈉。
另一方面,本發明提供了製備式(I)化合物或其鹽的製備方法,該等製備工藝包括濕法製粒、乾法製粒、直接混合等工藝,該等劑型包括片劑、膠囊。
較佳的,該等組合物是藉由濕法製粒完成的,該等方法包括以下步驟:(1)在濕法混合製粒機中預混合式I化合物或其鹽與部分潤滑劑,獲得預混合物;(2)添加製粒液體,較佳的,該等製粒液體為水,將步驟(1)的預混合物製粒;(3)在流化床乾燥器或乾燥箱中乾燥步驟(2)的顆粒;(4)任選的,乾燥篩分步驟(3)的乾燥的顆粒;(5)混合步驟(4)的乾燥的顆粒與剩餘賦形劑,獲得最終
混合物;(6)任選的,藉由合適的膠囊灌裝機灌裝上述步驟(5)的混合物,製備膠囊劑;(7)任選的,藉由在合適的壓片機上壓製上述步驟(5)的混合物,將其壓片,從而製得片芯;(8)任選的,用膜包衣對步驟(7)的片芯進行薄膜包衣。
較佳的,該等組合物是藉由乾法製粒完成的,該等方法包括以下步驟:(1)在料斗混合機中混合該等式I化合物或其鹽和包括黏合劑在內的大多數賦形劑,獲得預混合物;(2)在合適的滾筒壓製機中壓實步驟(1)的混合物;(3)藉由合適的研磨或篩分步驟,將步驟(2)期間獲得的帶狀物碎成顆粒;(4)任選的,在混合機中混合步驟(3)和剩餘賦形劑,獲得最終混合物;(5)任選的,藉由合適的膠囊灌裝機灌裝上述步驟(4)的混合物,製備膠囊劑;(6)任選的,藉由在合適的壓片機上壓製上述步驟(4)的混合物,將其壓片,從而製得片芯;(7)任選的,用膜包衣對步驟(6)的片芯進行薄膜包衣。
下面將結合具體實施例,對本發明的實施方案進行詳細描述。下面實施例僅用於說明本發明,而不應視為限定本發明的範圍。
將上述1000片處方量式I化合物和除硬脂酸鎂外其他賦形劑投入料斗混合機混勻,加潤濕劑潤濕製粒,45℃流化床乾燥10min,1.0mm篩整粒,加硬脂酸鎂總混10min,中控含量,灌裝膠囊。或壓製成片。
各處方在0.1mol/L HCl中溶出度,詳見下表。
將上述1000片處方量式I化合物和除硬脂酸鎂外其他賦形劑投入料斗混合機混勻,採用滾筒壓製機壓成帶狀物,將帶狀物碎成顆粒,加硬脂酸鎂總混10min,中控含量,灌裝膠囊。或壓製成片。
將上述1000片處方量式I化合物和賦形劑投入料斗
混合機混勻,中控含量,灌裝膠囊。或壓製成片。
將上述1000片處方量API和除硬脂酸鎂外其他賦形劑投入料斗混合機混勻,加潤濕劑潤濕製粒,流化床45℃乾燥10min,1.0mm篩整粒,加硬脂酸鎂總混10min,中控含量,灌裝膠囊。或壓製成片。
將上述1000片處方量API和除硬脂酸鎂外其他賦形劑投入料斗混合機混勻,採用滾筒壓製機壓成帶狀物,將帶狀物碎成顆粒,加硬脂酸鎂總混10min,中控含量,灌裝膠囊。或壓製成片。
將上述1000片處方量API和賦形劑投入料斗混合機混勻,中控含量,灌裝膠囊。或壓製成素片,包衣,控制包衣增重3%。
處方26-28,1000粒處方量API和賦形劑投入料斗混合機混勻,中控含量,灌裝膠囊。處方29-30,混合後直接壓製成素片,包衣,控制包衣增重3%。
處方31-32,1000粒處方量API和賦形劑投入料斗混合機混勻,中控含量,灌裝膠囊。處方33-34,混合後直
接壓製成素片,包衣,控制包衣增重3%。處方35,將式I化合物和除硬脂酸鎂外其他賦形劑投入料斗混合機混勻,採用滾筒壓製機壓成帶狀物,將帶狀物碎成顆粒,加硬脂酸鎂總混10min,中控含量,壓製成片,包衣,控制包衣增重3%。
將實施例8製備的膠囊採用市售包裝,在40℃±2℃、相對濕度75%±5%條件下,放置6個月,檢測結果見表1。
將式I化合物鹽和潤滑劑外賦形劑進行濕法製粒,乾燥後整粒,加潤滑劑總混10min,中控含量。處方36-38,灌裝膠囊,處方39-41,壓製成片,包衣,控制包衣增重3%。
Claims (16)
- 如申請專利範圍第1項所述的藥物組合物,其中,該等的稀釋劑係選自澱粉、糖粉、糊精、乳糖、預膠化澱粉、磷酸氫鈣、硫酸鈣、碳酸鈣、甘露醇、山梨醇或微晶纖維素中的至少一種。
- 如申請專利範圍第2項所述的藥物組合物,其中,該等的稀釋劑係選自乳糖、微晶纖維素、澱粉或甘露醇中的 至少一種。
- 如申請專利範圍第1項所述的藥物組合物,其中,該等的黏合劑係選自澱粉漿、羥丙甲纖維素、羥丙纖維素、聚維酮、甲基纖維素、羧甲基纖維素鈉或聚乙二醇的至少一種。
- 如申請專利範圍第4項所述的藥物組合物,其中,該等的黏合劑係選自羥丙基纖維素或聚維酮的至少一種。
- 如申請專利範圍第1項所述的藥物組合物,其中,該等的崩解劑係選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉、交聯聚維酮、乾澱粉或低取代羥丙基纖維素中的至少一種。
- 如申請專利範圍第6項所述的藥物組合物,其中,該等的崩解劑係選自交聯聚維酮、羧甲澱粉鈉、交聯羧甲基纖維素鈉中的至少一種。
- 如申請專利範圍第1項所述的藥物組合物,其中,該等潤滑劑係為硬脂酸鎂、硬脂酸、硬脂酸甘油酯、膠態二氧化矽、二氧化矽、滑石粉或山崳酸甘油酯中的至少一種。
- 如申請專利範圍第8項所述的藥物組合物,其中,該等潤滑劑係為硬脂酸、山崳酸甘油酯、膠態二氧化矽中的至少一種。
- 如申請專利範圍第1項所述的藥物組合物,其中,該等表面活性劑係為十二烷基硫酸鈉、吐溫80或泊洛沙姆188。
- 如申請專利範圍第10項所述的藥物組合物,其中,該等表面活性劑係為十二烷基硫酸鈉。
- 一種申請專利範圍第1項所述的式(I)化合物或其鹽的藥物組合物的製備方法,其中,係藉由濕法製粒製備,該等方法包括以下步驟:1)在濕法混合製粒機中預混合式(I)化合物或其鹽與部分賦形劑,獲得預混合物;2)添加製粒液體,將步驟1)的預混合物製粒;3)在流化床乾燥器或乾燥箱中乾燥步驟2)的顆粒;4)任選的,乾燥篩分步驟3)的乾燥的顆粒;5)混合步驟4)的乾燥的顆粒與剩餘賦形劑,獲得最終混合物;6)任選的,藉由合適的膠囊灌裝機灌裝上述步驟5)的混合物,製備膠囊劑;7)任選的,藉由在合適的壓片機上壓製上述步驟5)的混合物,將其壓片,從而製得片芯;8)任選的,用膜包衣對步驟7)的片芯進行薄膜包衣。
- 如申請專利範圍第12項所述的製備方法,其中,該等製粒液體為水。
- 一種申請專利範圍第1項所述的式(I)化合物或其鹽的藥物組合物的製備方法,其中,係藉由乾法製粒完成的,該等方法包括以下步驟:1)在料斗混合機中混合該等式(I)化合物或其鹽和部分賦形劑,獲得預混合物; 2)在合適的滾筒壓製機中壓實步驟1)的混合物;3)藉由合適的研磨或篩分步驟,將步驟2)期間獲得的帶狀物碎成顆粒;4)任選的,在混合機中混合步驟3)和剩餘賦形劑,獲得最終混合物;5)任選的,藉由合適的膠囊灌裝機灌裝上述步驟4)的混合物,製備膠囊劑;6)任選的,藉由在合適的壓片機上壓製上述步驟4)的混合物,將其壓片,從而製得片芯;7)任選的,用膜包衣對步驟6)的片芯進行薄膜包衣。
- 一種申請專利範圍第1項所述的式(I)化合物或其鹽的藥物組合物的製備方法,其中,該等藥物組合物係藉由直接混合的方法製得。
- 如申請專利範圍第14項所述的製備方法,其中,該等方法係包括以下步驟:1)在料斗混合機中混合該等式(I)化合物或其鹽和其他所有賦形劑,獲得混合物;2)任選的,藉由膠囊灌裝機灌裝上述步驟1)的混合物,製備膠囊劑;3)任選的,藉由在合適的壓片機上壓製上述步驟1)的混合物,將其壓片,從而製得片芯;4)任選的,用膜包衣對步驟3)的片芯進行薄膜包衣。
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EP3186252A1 (en) * | 2014-08-28 | 2017-07-05 | ratiopharm GmbH | Method of producing palbociclib and pharmaceutical compositions comprising the same |
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- 2014-11-07 CN CN201410623810.2A patent/CN105616418A/zh active Pending
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2015
- 2015-11-06 TW TW104136656A patent/TWI704918B/zh not_active IP Right Cessation
- 2015-11-06 EP EP15857367.5A patent/EP3216450B1/en active Active
- 2015-11-06 JP JP2017521077A patent/JP6682739B2/ja not_active Expired - Fee Related
- 2015-11-06 CN CN201580043546.8A patent/CN106794183B/zh active Active
- 2015-11-06 WO PCT/CN2015/093953 patent/WO2016070834A1/zh active Application Filing
- 2015-11-06 US US15/524,394 patent/US20180280392A1/en not_active Abandoned
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Also Published As
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CN105616418A (zh) | 2016-06-01 |
US20180280392A1 (en) | 2018-10-04 |
EP3216450A8 (en) | 2018-02-07 |
WO2016070834A1 (zh) | 2016-05-12 |
CN106794183A (zh) | 2017-05-31 |
EP3216450A4 (en) | 2018-06-13 |
TW201617082A (zh) | 2016-05-16 |
EP3216450B1 (en) | 2021-09-22 |
JP2017532347A (ja) | 2017-11-02 |
CN106794183B (zh) | 2021-06-18 |
JP6682739B2 (ja) | 2020-04-15 |
EP3216450A1 (en) | 2017-09-13 |
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