TW201617082A - 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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Abstract
本發明涉及一種以6-乙醯基-8-環戊基-5-甲基-2-(5-呱□-1-基-吡啶-2-基胺基)-8H-吡啶并[2,3-d]嘧啶-7-酮或其鹽為活性成分的藥物製劑，該等鹽包括鹽酸鹽、羥乙基磺酸鹽，該等藥物劑型包括片劑、膠囊劑。該等劑型均具有良好的穩定性以及優異的溶出行為。
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。
本發明的目的在於提供一種含有6-乙醯基-8-環戊基-5-甲基-2-(5-呱-1-基-吡啶-2-基胺基)-8H-吡啶并[2,3-d]嘧啶-7-酮及鹽的藥物製劑及其製備方法。
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%。
較佳的，該等組合物包括式I化合物或其鹽及賦形劑，該等賦形劑包括崩解劑、稀釋劑、黏合劑、表面活性劑、潤滑劑中一種或多種，較佳的，各組分重量比如下：
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%。
進一步較佳的，該等的藥物製劑，各組分的重量百分比如下：
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%。
更佳的，該等的藥物製劑，各組分的重量百分比如下：
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。
本發明提供了一種穩定的，適合醫藥應用的6-乙醯基-8-環戊基-5-甲基-2-(5-呱-1-基-吡啶-2-基胺基)-8H-吡啶并[2,3-d]嘧啶-7-酮及鹽的藥物製劑，該藥物製劑具有優異的溶出行為和好的穩定性，符合臨床應用需
求，能夠使活性成分實現良好的體內生物利用度。
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 (14)
- 一種式(I)化合物或其鹽的藥物組合物，其係包括式I化合物或其鹽，以及藥學上可接受的賦形劑作為載體，該等鹽係選自鹽酸鹽或羥乙基磺酸鹽，
- 如申請專利範圍第1項所述的藥物組合物，其中，該等化合物I或其鹽係占該等藥物組合物重量的10%至80%，較佳係15至60%，進一步較佳係20至40%。
- 如申請專利範圍第1項所述的藥物組合物，其中，該等賦形劑係選自崩解劑、稀釋劑、黏合劑、表面活性劑或潤滑劑中一種或多種，較佳的，該等藥物組合物中各組分重量百分比如下：
- 如申請專利範圍第3項所述的藥物組合物，其中，該等藥物組合物中各組分的重量百分比係如下：
- 如申請專利範圍第4項所述的藥物組合物，其中，該等藥物組合物中各組分的重量百分比係如下：
- 如申請專利範圍第3至5項中任意一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，較佳係乳糖、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3至5項中任意一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，較佳係羥丙基纖維素或聚維酮的至少一種。
- 如申請專利範圍第3至5項中任意一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，較佳係交聯聚維酮、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3至5項中任意一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，較佳係硬脂酸、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3至5項中任意一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，較佳係十二烷基硫酸鈉。
- 一種式(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，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。
- 一種式(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12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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| US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| CN110314148A (zh) * | 2019-05-07 | 2019-10-11 | 安徽金太阳生化药业有限公司 | 一种磷酸氢钙片的制备方法 |
| WO2022063119A1 (zh) * | 2020-09-24 | 2022-03-31 | 南京济群医药科技股份有限公司 | 一种羟乙磺酸哌柏西利的组合物及药物 |
| CN114306245A (zh) | 2020-09-29 | 2022-04-12 | 深圳市药欣生物科技有限公司 | 无定形固体分散体的药物组合物及其制备方法 |
| CN117298115A (zh) * | 2022-11-18 | 2023-12-29 | 轩竹生物科技股份有限公司 | CDKs抑制剂的药物组合物及制备方法 |
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| US20010007863A1 (en) * | 1998-06-18 | 2001-07-12 | Merck & Co., Inc. | Wet granulation formulation for bisphosphonic acids |
| KR20060111716A (ko) * | 2002-01-22 | 2006-10-27 | 워너-램버트 캄파니 엘엘씨 | 2-(피리딘-2-일아미노)-피리도[2,3-ｄ]피리미딘-7-온 |
| EP1648889B1 (en) * | 2003-07-11 | 2008-10-29 | Warner-Lambert Company LLC | Isethionate salt of a selective cdk4 inhibitor |
| WO2008057267A2 (en) * | 2006-10-27 | 2008-05-15 | Fmc Corporation | Co-processed microcrystalline cellulose and sugar alcohol as an excipient for tablet formulations |
| TW201129386A (en) * | 2009-11-05 | 2011-09-01 | Fmc Corp | Microcrystalline cellulose and calcium phosphate compositions useful as pharmaceutical excipients |
| DK2958916T3 (en) * | 2013-02-21 | 2018-11-12 | Pfizer | Solid forms of a selective CDK4 / 6 inhibitor |
| EP3186252A1 (en) * | 2014-08-28 | 2017-07-05 | ratiopharm GmbH | Method of producing palbociclib and pharmaceutical compositions comprising the same |
| KR102068423B1 (ko) * | 2015-06-04 | 2020-01-20 | 화이자 인코포레이티드 | 팔보시클립의 고체 투여 형태 |
| CN104892604B (zh) * | 2015-06-19 | 2016-08-24 | 北京康立生医药技术开发有限公司 | 一种cdk4抑制剂的合成方法 |
| CN105213322A (zh) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | 一种干法制粒工艺制备的药物组合物 |
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| CN106794183A (zh) | 2017-05-31 |
| CN106794183B (zh) | 2021-06-18 |
| EP3216450B1 (en) | 2021-09-22 |
| JP2017532347A (ja) | 2017-11-02 |
| EP3216450A8 (en) | 2018-02-07 |
| US20180280392A1 (en) | 2018-10-04 |
| TWI704918B (zh) | 2020-09-21 |
| EP3216450A1 (en) | 2017-09-13 |
| WO2016070834A1 (zh) | 2016-05-12 |
| JP6682739B2 (ja) | 2020-04-15 |
| CN105616418A (zh) | 2016-06-01 |
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