CN112294810B - 含有西达本胺和表面活性剂的药物组合物 - Google Patents
含有西达本胺和表面活性剂的药物组合物 Download PDFInfo
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- CN112294810B CN112294810B CN202010741136.3A CN202010741136A CN112294810B CN 112294810 B CN112294810 B CN 112294810B CN 202010741136 A CN202010741136 A CN 202010741136A CN 112294810 B CN112294810 B CN 112294810B
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- surfactant
- pharmaceutical composition
- sodium
- preparation
- sulfonate
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
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Abstract
本发明公开了一种含有西达本胺和表面活性剂的药物组合物。本发明公开的含有西达本胺和表面活性剂的药物组合物具有显著提高的生物利用度。
Description
技术领域
本发明涉及医药技术领域，具体涉及含有西达本胺和表面活性剂的药物组合物及其应用。
背景技术
西达本胺具有下式(1)结构，其化学名称为N-(2-氨基-4-氟苯基)-4-[N-[(E)-3-(3-吡啶)丙烯酰基]氨甲基]苯甲酰胺。在其结构式中，3-吡啶丙烯酰基的构型为E型。
西达本胺是深圳微芯生物科技股份有限公司独家发现的新分子实体药物，机制新颖，是全球首个亚型选择性组蛋白去乙酰化酶(HDAC)抑制剂和全球首个获批治疗外周T细胞淋巴瘤的口服药物，属于表观遗传调控剂类药物。
在抗肿瘤治疗领域，尽管各类新型靶向抗肿瘤药物的应用使肿瘤治疗的有效率提升，无进展生存期(PFS)时间得到延长，但是肿瘤的耐药性产生、转移和复发仍是难以逾越的障碍。在多数肿瘤中，患者的长期生存率并没有得到特别显著的改善，超过90％的肿瘤患者最终死于肿瘤的转移和复发，这主要源于肿瘤的免疫逃逸、肿瘤的异质性、干细胞样和肿瘤耐药性。而近十年来，大量的科学研究发现表观遗传在克服肿瘤免疫逃逸，诱导与肿瘤复发相关的肿瘤干细胞的分化，逆转与肿瘤转移密切相关的上皮间充质细胞表型转化以及清除异质性肿瘤中的耐药性细胞等分子作用方面扮演了十分重要的角色。因此，表观遗传药物(Epidrugs)成为当前药物研发领域的一个重要热点。
西达本胺属于表观遗传调控剂药物，具有对肿瘤发生发展相关的表观遗传异常的重新调控作用，作用于表观遗传相关靶点-组蛋白去乙酰化酶(第I类的1、2、3亚型和第IIb类的10亚型)。组蛋白去乙酰化酶(HDAC)是一类对染色体的结构修饰和基因表达调控发挥重要作用的蛋白酶，西达本胺作为HDAC抑制剂，通过抑制HDAC的生物学活性产生作用，并由此产生针对肿瘤发生的多条信号传递通路基因表达的改变(即表观遗传改变)。
然而，西达本胺在水中的溶解度极小，严重影响了其生物利用度。因此，现有技术中仍迫切需要提高西达本胺的生物利用度。
CN201310364845.4公开了一种西达苯胺固体分散制剂，含有活性成分以及聚乙烯吡咯烷酮(PVP)，其声称具有提高的生物利用度，然而没有任何证据表明所述制剂具有令人满意的生物利用度。
CN201410016221.8公开了一种西达本胺固体分散体，其中西达本胺与水溶性载体材料的重量比为1:1～1:20，特别公开了西达本胺与聚维酮K30按重量比为1:5制成的固体分散体。事实上，市售西达本胺固体分散体片剂采用的即是该配方。
CN201610855106.9公开了一种西达本胺的稳定的固体分散体，其包含西达本胺和共聚维酮。
现有技术中仍需要进一步提高西达本胺的生物利用度，因此，仍迫切需要提供一种具有提高的生物利用度的西达本胺药物组合物。
发明内容
有鉴于此，本发明的目的是针对现有技术的不足，提供一种具有显著提高的生物利用度的西达本胺药物组合物。
本发明人意外发现，通过加入表面活性剂，可以显著提高西达本胺的生物利用度。
因此，在第一个方面，本发明提供了一种药物组合物，其含有西达本胺和表面活性剂。优选地，所述药物组合物中西达本胺和所用表面活性剂的质量比为1:0.1～1:10，更优选1:0.5～1:5。
在本发明的药物组合物中，所述表面活性剂优选选自阴离子表面活性剂和两性离子表面活性剂。
在一些优选的实施方案中，所述阴离子表面活性剂选自高级脂肪酸盐、硫酸化物和磺酸化物，更优选选自硫酸化物和磺酸化物，进一步优选选自十二烷基硫酸钠、十二烷基磺酸钠、硬脂酸镁、二己基琥珀酸磺酸钠和二辛基琥珀酸磺酸钠；所述两性离子表面活性剂选自卵磷脂、氨基酸型两性离子表面活性剂和甜菜碱型两性离子表面活性剂，更优选为卵磷脂。
本发明还提供了所述西达本胺药物组合物的制备方法，包括将西达本胺与表面活性剂混合均匀的步骤。任选地，可将混合均匀后的西达本胺和表面活性剂进行粉碎过筛，再与任选地填充剂混合，干法制粒后将所得颗粒与崩解剂、粘合剂混合，所得混合物经压片可制得片剂；其中所述西达本胺与所用表面活性剂的质量比为1:0.1～1:10。所述表面活性剂可选自阴离子表面活性剂和/或两性离子表面活性剂。
阴离子表面活性剂
本发明的阴离子表面活性剂系指在水中电离后起表面活性作用的是阴离子。作为本发明的阴离子表面活性剂的具体例，例如可以举出脂肪酸盐、硫酸化物、磺酸化物、磷酸酯盐、氨基酸盐、酚盐、烯醇盐、酮基磺胺盐等等。本领域技术人员公知，作为阴离子表面活性剂的高级脂肪酸盐系肥皂类，通式为(RCOO-)nMn+，其中脂肪酸烃链R一般在C11～C17之间，以硬脂酸、油酸、月桂酸等较常见。作为阴离子表面活性剂的硫酸化物是硫酸化油和高级脂肪醇硫酸酯类，通式为R·O·SO3 －M+，其中脂肪烃链R在C12～C18范围内。作为阴离子表面活性剂的磺酸化物系指脂肪族磺酸化物和烷基芳基磺酸化物等，通式分别为R·SO3 -M+和RC6H5·SO3 -M+。其中，优选所述阴离子表面活性剂选自高级脂肪酸盐、硫酸化物和磺酸化物，更优选地，所述阴离子表面活性剂选自硫酸化物和磺酸化物；特别优选地，选自十二烷基硫酸钠，十二烷基磺酸钠，硬脂酸镁，二己基琥珀酸磺酸钠和二辛基琥珀酸磺酸钠。
两性离子表面活性剂
本发明的两性离子表面活性剂系指分子结构中同时具有正、负电荷基团，因而同时具有两种离子性质。作为本发明的两性离子表面活性剂的具体例，例如可以举出氨基酸型、甜菜碱型、咪唑啉型和氧化胺型。其中，优选所述两性离子表面活性剂选自卵磷脂、氨基酸型两性离子表面活性剂和甜菜碱型两性离子表面活性剂，更优选卵磷脂。卵磷脂根据来源不同称为豆磷脂或蛋磷脂。
特别优选地，在本发明的药物组合物中，所述表面活性剂选自十二烷基硫酸钠、十二烷基磺酸钠、十八烷基硫酸钠、卵磷脂、二己基琥珀酸磺酸钠和二辛基琥珀酸磺酸钠。尤其优选地，在本发明的药物组合物中，所述表面活性剂选自十二烷基硫酸钠、十二烷基磺酸钠、十八烷基硫酸钠、卵磷脂和二辛基琥珀酸磺酸钠。
在本发明的药物组合物中，西达本胺和所用表面活性剂的质量比为1:0.1～1:10，更优选1:0.5～1:5。
本发明的药物组合物可以是药物制剂、尤其是口服制剂的形式。在一些优选的方面，本发明的药物组合物为选自以下的药物制剂形式：片剂、胶囊剂、软胶囊剂、丸剂、口服液体制剂、颗粒剂、散剂、膏剂、滴丸剂。所述药物制剂优选片剂和胶囊剂，优选缓释制剂或控释制剂。
在一些实施方案中，本发明的药物组合物可以含有填充剂、崩解剂、粘合剂和/或润滑剂，其中所述填充剂选自乳糖、微晶纤维素和甘露醇；所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠和羧甲基淀粉钠；所述粘合剂选自羧甲基纤维素钠、羟丙纤维素、乙基纤维素和聚乙烯吡咯烷酮；所述润滑剂选自硬脂酸、硬脂酸镁、硬酯富马酸钠、聚乙二醇、微粉硅胶和滑石粉。
本发明的药物组合物还可以含有其他辅料，可以通过常规方法制备成口服制剂。
作为优选，所述填充剂选自乳糖、玉米淀粉、羟丙甲基纤维素、羟丙基纤维素、十六醇、十八醇、乙基纤维素、预胶化淀粉、蔗糖、微晶纤维素、甘露醇、磷酸氢钙、磷酸钙、黄原胶和胶体二氧化硅。
作为优选，所述崩解剂选自淀粉、微晶纤维素、交联羧甲基纤维素钠、羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮和低取代羟丙基纤维素。
作为优选，所述粘合剂选自水、乙醇、羟丙基纤维素、羟丙甲基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮和共聚维酮。
作为优选，所述润滑剂选自硬脂酸、硬脂酸镁、硬酯富马酸钠、聚乙二醇4000-8000、微粉硅胶和滑石粉。
本发明还提供了所述药物组合物在制备用于治疗与组蛋白去乙酰化酶作用机制相关的疾病的药物中的应用，其中所述与组蛋白去乙酰化酶作用机制相关的疾病优选选自癌症、病毒性疾病、自身免疫疾病和血液系统疾病。
在另一方面，本发明还提供了一种提高西达本胺生物利用度的方法，包括将西达本胺与表面活性剂混合的步骤。优选地，所述表面活性剂选自阴离子表面活性剂和两性离子表面活性剂。更优选地，所述表面活性剂选自十二烷基硫酸钠、十二烷基磺酸钠、十八烷基硫酸钠、卵磷脂、二己基琥珀酸磺酸钠和二辛基琥珀酸磺酸钠。特别优选地，所述表面活性剂选自十二烷基硫酸钠、十二烷基磺酸钠、十八烷基硫酸钠、卵磷脂和二辛基琥珀酸磺酸钠。
需要说明的是，在本文中，术语“选自”后列举若干元素、要素或成员时，其表示可以包括这些元素、要素或成员的一个，也可以包括这些元素、要素或成员的任意组合。
本发明的有益效果
本发明所述西达本胺药物组合物包含西达本胺和表面活性剂。本发明所述西达本胺药物组合物大大改善了西达本胺的水溶性，与市售西达本胺制剂相比，具有更高的生物利用度。
附图说明
图1所示为西达本胺药物组合物大鼠药代实验结果。
图2所示为西达本胺药物制剂比格犬药代实验结果。
具体实施方式
本发明公开了西达本胺药物组合物及其制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用和药用组合物已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用和药用组合物进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的一种药用组合物及其制备方法做进一步说明。
对照实施例1：西达本胺固体分散体的制备
处方：
西达本胺 2g 16.67％
聚乙烯吡咯烷酮K30 10g 83.33％
乙醇 适量 ---
制备方法如下：
(1)准确称量西达本胺和聚乙烯吡咯烷酮K30，90℃水浴，溶于适量乙醇中，形成透明溶液；
(2)将步骤(1)形成的溶液90℃旋蒸，干燥，形成固体分散体；
(3)将步骤(2)所得的固体分散体取出粉碎，制备成西达本胺固体分散体粉末。
制备实施例2：西达本胺-十二烷基硫酸钠(1:1.5)组合物的制备
处方：
西达本胺 2g 40.00％
十二烷基硫酸钠 3g 60.00％
制备方法如下：
(1)准确称量西达本胺和十二烷基硫酸钠于封口袋中；
(2)将步骤(1)的组合物混合20min，混合均匀，形成西达本胺-十二烷基硫酸钠组合物。
制备实施例3：西达本胺-十二烷基磺酸钠(1:3)组合物的制备
处方：
西达本胺 2g 25.00％
十二烷基磺酸钠 6g 75.00％
制备方法如下：
(1)准确称量西达本胺和十二烷基磺酸钠于封口袋中；
(2)将步骤(1)的组合物混合20min，混合均匀，形成西达本胺-十二烷基磺酸钠组合物。
生物活性实施例4：西达本胺药物组合物的大鼠药代动力学研究
选择健康大鼠18只，随机分成3组，每组6只(雌性3只，雄性3只)，分别为西达本胺固体分散体组(对照实施例1)、西达本胺-十二烷基硫酸钠(1:1.5)组合物组(制备实施例2)、西达本胺-十二烷基磺酸钠(1:3)组合物组(制备实施例3)。试验期间，大鼠给药前禁食过夜，给药前眼眶取血，分离血浆，作为0h的血药浓度样品。灌胃液采用纯化水分散，灌胃液为浓度2mg/ml，每只大鼠分别灌服剂量西达本胺20mg/kg。给药后，分别在15min，0.5h，1h，2h，4h，6h，8h采集血样，每个样品采集约0.5ml，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆，-80℃保存待测。用LC-MS/MS测其血浆中药物浓度。检测结果见表1和图1。
表1大鼠药代数据对比表
| 参数(ng/ml) | 对照实施例1 | 制备实施例2 | 制备实施例3 |
| AUC(0-t) | 2714.0 | 5300.6 | 5267.2 |
| Cmax | 785.0 | 2610.9 | 2151.0 |
根据表1和图1的检测结果可见，与西达本胺固体分散体片相比，含有十二烷基硫酸钠或十二烷基磺酸钠的西达本胺剂组合物，能显著提高西达本胺的生物利用度。
为进一步验证含有表面活性剂和西达本胺剂的药物组合物确实能够提高西达本胺的生物利用度，还进行了成型制剂在比格犬体内的药代动力学研究。
制备实施例5：西达本胺-十二烷基硫酸钠药物组合物(1:0.5)的制备
处方(1000片)：
制备方法如下：
(1)将十二烷基硫酸钠、西达本胺准确称量，加入适量水中，搅拌均匀得混悬液；
(2)称量微晶纤维素、乳糖、羧甲基纤维素钠、羟丙甲基纤维素并混合均匀；
(3)将步骤(1)混悬液加入到步骤(2)混合物中，湿法制粒干燥，整粒；
(4)所得干燥的颗粒经压片可制得片剂。
制备实施例6：西达本胺-十八烷基硫酸钠药物组合物(1:1)的制备
处方(1000片)
制备方法如下：
(1)将十八烷基硫酸钠、西达本胺混合均匀，进行过筛；
(2)与微晶纤维素、甘露醇混合，干法制粒；
(3)将所得颗粒与羧甲基淀粉钠、聚乙烯吡咯烷酮混合；
(4)所得混合物经压片可制得片剂。
制备实施例7：西达本胺-十二烷基磺酸钠药物组合物(1:3)的制备
处方(1000片)：
制备方法如下：
(1)将十二烷基磺酸钠、西达本胺准确称量，加入适量水中，搅拌均匀得混悬液；
(2)称量微晶纤维素、甘露醇、羧甲基淀粉钠、聚乙烯吡咯烷酮，投料到流化床中，进行流化床制粒、干燥；
(3)对流化床所得颗粒进行整粒；
(4)所得颗粒经压片可制得片剂。
对照实施例8：西达本胺-泊洛沙姆188药物组合物(1:5)的制备
处方(1000片)：
制备方法如下：
(1)将泊洛沙姆188、西达本胺混合均匀，进行粉碎过筛；
(2)将上述混合物与预胶化淀粉、甘露醇、羟丙基纤维素、交联聚乙烯吡咯烷酮混合均匀，加水进行湿法制粒，制得软材；
(3)将上述软材进行干燥，整粒；
(4)所得颗粒经压片可制得片剂。
制备实施例9：西达本胺-卵磷脂药物组合物(1:5)的制备
处方
制备方法如下：
(1)将卵磷脂、西达本胺准确称量，加入适量水中，搅拌均匀得混悬液；
(2)称量玉米淀粉、磷酸钙、低取代羟丙基纤维素、共聚维酮并混合均匀；
(3)将步骤1混悬液加入到步骤2混合物中，湿法制粒干燥，整粒；
(4)所得干燥的颗粒装袋得颗粒剂。
制备实施例10：西达本胺-二己基琥珀酸磺酸钠组合物(1:8)的制备
处方(1000片)：
制备方法如下：
(1)将二己基琥珀酸磺酸钠、西达本胺加适量水混合均匀；
(2)与微晶纤维素、甘露醇混合，湿法制粒；
(3)将所得颗粒与羧甲基淀粉钠、共聚维酮混合；
(4)所得混合物经压片可制得片剂。
制备实施例11：西达本胺-二辛基琥珀酸磺酸钠药物组合物(1:10)的制备
处方(1000片)
制备方法如下：
(1)将微晶纤维素加水制得软材，使用挤出滚圆法制得空白丸芯，干燥，过筛；
(2)将西达本胺、二辛基琥珀酸磺酸钠、聚乙烯吡咯烷酮、水配成含西达本胺的包衣液；
(3)将空白丸芯置于流化床中，用上述包衣液在空白丸芯上包衣，得到载药微丸干燥，过筛，将载药微丸装填于空胶囊壳中，即得胶囊。
生物活性实施例12：西达本胺药物组合物的比格犬药代动力学研究
选择健康比格犬15条，随机分成5组，每组三只，分别为市售西达本胺片剂组、实施例6组、实施例8组、实施例9组和实施例11组。试验期间，比格犬给药前禁食过夜(10-14小时)，给药前采集静脉血，分离血浆，作为0h的血药浓度样品。每条犬分别灌服西达本胺20mg(4粒，5mg/粒)。给药后，分别在15min，0.5h，1h，2h，4h，8h采集血样，每个样品采集约0.5ml，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆，-80℃保存待测。用LC-MS/MS测其血浆中药物浓度。检测结果见表2和图2。
表2 LC-MS/MS测定不同时间点的各组犬血浆中药物浓度(ng/mL)
根据表2和图2的检测结果可见，与市售的西达本胺固体分散体片剂(注册商标爱谱沙)以及含有非离子表面活性剂泊洛沙姆188的西达本胺药物组合物相比，含有阴离子表面活性剂和两性离子表面活性剂的西达本胺药物组合物，能显著提高西达本胺的生物利用度。
Claims (2)
1.一种药物组合物，其含有西达本胺和表面活性剂，
其为选自以下的口服制剂：
(1)具有以下重量组成的片剂：
(2)具有以下重量组成的颗粒剂：
(3)具有以下重量组成的胶囊：
2.根据权利要求1的药物组合物在制备用于治疗与组蛋白去乙酰化酶作用机制相关的疾病的药物中的应用，其中所述与组蛋白去乙酰化酶作用机制相关的疾病选自癌症、病毒性疾病、自身免疫疾病和血液系统疾病。
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| CN1371366A (zh) * | 1999-08-30 | 2002-09-25 | 先灵公司 | 具有组蛋白脱乙酰酶抑制剂活性的苯甲酰胺制剂 |
| CN103833626A (zh) * | 2012-11-27 | 2014-06-04 | 深圳微芯生物科技有限责任公司 | 西达本胺的晶型及其制备方法与应用 |
| CN104771363A (zh) * | 2014-01-14 | 2015-07-15 | 深圳微芯生物科技有限责任公司 | 一种西达本胺固体分散体及其制备方法与应用 |
| WO2016205695A1 (en) * | 2015-06-19 | 2016-12-22 | Faller Douglas V | Methods and compositions for treating herpesvirus induced conditions |
| CN106821965A (zh) * | 2015-12-04 | 2017-06-13 | 中国科学院大连化学物理研究所 | 一种维甲酸多药共递送纳米粒溶液及其制备和应用 |
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| CN101112541A (zh) * | 2006-07-25 | 2008-01-30 | 复旦大学 | 艾替卡韦药物组合物及其用途 |
| CN114681455A (zh) * | 2018-08-17 | 2022-07-01 | 深圳微芯生物科技股份有限公司 | 组蛋白去乙酰化酶抑制剂与蛋白激酶抑制剂之组合及其制药用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1371366A (zh) * | 1999-08-30 | 2002-09-25 | 先灵公司 | 具有组蛋白脱乙酰酶抑制剂活性的苯甲酰胺制剂 |
| CN103833626A (zh) * | 2012-11-27 | 2014-06-04 | 深圳微芯生物科技有限责任公司 | 西达本胺的晶型及其制备方法与应用 |
| CN104771363A (zh) * | 2014-01-14 | 2015-07-15 | 深圳微芯生物科技有限责任公司 | 一种西达本胺固体分散体及其制备方法与应用 |
| WO2016205695A1 (en) * | 2015-06-19 | 2016-12-22 | Faller Douglas V | Methods and compositions for treating herpesvirus induced conditions |
| CN106821965A (zh) * | 2015-12-04 | 2017-06-13 | 中国科学院大连化学物理研究所 | 一种维甲酸多药共递送纳米粒溶液及其制备和应用 |
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