CN114524769B - 塞来昔布-卡马西平共晶、制备方法、药物组合物和应用 - Google Patents
塞来昔布-卡马西平共晶、制备方法、药物组合物和应用 Download PDFInfo
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- CN114524769B CN114524769B CN202210133761.9A CN202210133761A CN114524769B CN 114524769 B CN114524769 B CN 114524769B CN 202210133761 A CN202210133761 A CN 202210133761A CN 114524769 B CN114524769 B CN 114524769B
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- carbamazepine
- celecoxib
- crystal
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Abstract
本发明公开了一种塞来昔布‑卡马西平共晶、制备方法药物组合物和应用。该共晶中塞来昔布与卡马西平的摩尔比为1:2～2:1。该共晶及其药物组合物在保留了塞来昔布和卡马西平分子结构和生物活性的基础上，具有优异的协同溶出‑释放性质，使药物具有更优异的临床应用效果，并且该共晶制备方法简便、易操作，制备所得的共晶纯度高，并开发了适于工业化规模的制备方法。
Description
技术领域
本发明涉及一种塞来昔布-卡马西平共晶、制备方法、药物组合物和应用，尤其涉及一种具有优异的溶出-释放性质、安全有效、制备便捷的塞来昔布-卡马西平共晶、制备方法、药物组合物和应用。
背景技术
癫痫是一类中枢系统疾病，是世界卫生组织报导的难治性疾病之一，其具体发病机制仍不清楚。相当比例的患者对抗癫痫药物产生耐药，难以控制。卡马西平(Carbamazepine，CBZ)为抗癫痫、抗惊厥药，药理作用表现为抗惊厥、抗癫痫、抗神经性疼痛、抗躁狂-抑郁症、改善某些精神疾病的症状、抗中枢性尿崩症。卡马西平属于BCS II类药物，几乎不溶于水(120μg/ml，25℃)。卡马西平在人体内溶解、溶出速率缓慢，导致药物在胃肠道中吸收不规则，生物利用度低。服用卡马西平片剂后血药浓度的个体差异大，且与口服剂量不相关。通常成人单独使用时有效治疗浓度为4～12μg/ml，在此浓度下60％以上的相关运动性发作可得以控制，血药浓度超过12～20μg/ml时，往往产生严重的毒副作用，并加重癫痫发作。由于血药浓度与剂型、疗效和毒副作用的相关性，以及患者的用药依从性，维持稳定的血药浓度，提高用药患者的依从性对提高疗效和减少毒副作用是非常必要的。
通过对癫痫耐药的机制进行深入研究，发现癫痫患者的耐药与P糖蛋白(P-gp)对抗癫痫药物的外排有很大关联。而P-gp的过度表达又被证明与COX-2有关。塞来昔布(Celecoxib，CEL)是环氧合酶2(COX-2)选择性抑制剂，临床上主要用于抗炎镇痛，主要适应症为骨关节炎、风湿性关节炎等。作为具有高度选择性的COX抑制剂，塞来昔布对COX-1的亲和力极弱，因此，塞来昔布不仅具有与传统抗炎药类似的镇痛抗炎作用，而且胃肠道不良反应明显下降。但已有的塞来昔布胶囊与片剂半衰期短，患者用药依从性不高，同时由于睡眠时间等因素的影响，影响药物稳态血药浓度，从而影响药效。
目前，已有临床实验以口服卡马西平作为对照组，同时口服塞来昔布和卡马西平为观察组，结果观察组抑制癫痫效果显著。此外，有研究发现塞来昔布对常染色体显性侧颞叶癫痫有显著抑制作用，将塞来昔布与卡马西平组合联用有利于实现对癫痫的控制。然而，将多个药物组合联用也会面临一些挑战，比如药物之间的稳定性、溶解性差异、不相容等，寻求一种可替代的多药联用策略是非常必要的。
发明内容
发明目的：针对卡马西平单药使用时存在的生物利用度低、毒副作用大、病人依从性差，塞来昔布单药使用时存在的半衰期短、病人依从性差以及多药联用时存在的药物之间的稳定性不佳、溶解性差异大、相容性欠佳等不足，本发明旨在提供一种具有优异的药物协同溶解-释放特性的塞来昔布-卡马西平共晶、制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的塞来昔布-卡马西平共晶中塞来昔布与卡马西平的摩尔比为1:2～2:1。
多药疗法是目前复杂疾病(艾滋病、肿瘤、心血管、感染性疾病等)的主流治疗方法，其原理是综合多个药物的作用机制、药代动力学、药物毒理学、药物之间的相互作用和药物副作用等，从而设计合理的药物组合。在设计过程中，往往容易忽略药物的基本理化性质，如药物之间的溶解度差异，会进一步导致不能协同释放，存在影响药效和毒副作用的风险。共晶是两个或两个以上的分子以特定的化学比例通过弱相互作用如非共价键(氢键、π-π堆积等)连接的固态单相体系，该体系无电荷转移，也不是溶剂合物。当共晶中的两个组分为药物活性成分时，该体系称之为药药共晶。药药共晶作为一种新型的多药联用形式，相对于简单的多药联用方式而言，能够在不影响药效活性的前提下，有效调节药物的释放速率等理化性质，更有利于药物组合的设计。
本发明通过药药共结晶策略，首次将具有联用价值的塞来昔布和卡马西平构建成为塞来昔布与卡马西平的药药共晶，提供了一种利于成药、并能降低塞来昔布的心血管毒副作用及增强抗癫痫效果、能对两个药物的溶出速率进行调控的药物，从而减小了两个药物的溶解度差异。经溶出性质考察，所述的塞来昔布与卡马西平的药药共晶能够加快塞来昔布的溶出，延缓卡马西平的释放，有利于协同释放。其具有基本如图5所示的固有溶出曲线。
具体地，所述共晶为三斜晶系空间群，晶胞参数为：/> 轴角α＝88.950(4)°，β＝88.996(4)°，γ＝84.532(5)°。其具有基本如图1所示的晶体结构。
更具体地，以衍射角2θ±0.2°表示，所述共晶在6.18°，7.22°，9.64°，10.44°，12.08°，12.44°，14.28°，14.46°，15.60°，16.34°，17.02°，17.62°，18.20°，18.88°，19.60°，19.86°，20.16°，20.76°，20.90°，21.36°，21.78°，21.96°，22.48°，24.66°处至少具有一个特征衍射峰。其具有基本如图2所示的X-射线粉末衍射(PXRD)图谱。
更具体地，所述共晶在148.6℃±0.2℃处具有特征熔融峰。其具有基本如图3所示的差示扫描量热分析(DSC)谱图，也具有基本如图4所示的热重分析(TGA)图谱。
药药共晶的制备方法有溶液法和固态法，溶液法是指通过加入大量溶剂结晶制备药药共晶，具体包括混悬搅拌、缓慢挥发、冷却结晶等，相对于其它方法，该法制备的产物纯度更高、不易降解等优点。固态法包括通过不添加溶剂或仅添加少量易挥发溶剂辅助制备药药共晶，具体包括机械研磨、熔融法等，该法的优势在于无溶剂或少量溶剂的存在，相对于溶液合成法更安全、更环保。值得一提的是，目前对于药药共晶的制备，多以实验室制备为主，更进一步地工业放大生产药药共晶的方法比较稀缺，因此，发明一种药药共晶的放大制备方法有利于后续药药共晶的产品开发。
作为本发明涉及的第二方面，上述塞来昔布-卡马西平共晶的制备方法为以下任一方法：
(1)方法一：将塞来昔布与卡马西平溶解，过滤后，移除溶剂结晶；
(2)方法二：将塞来昔布与卡马西平形成混悬液，搅拌，移除溶剂；
(3)方法三：将塞来昔布与卡马西平混合，加热熔融，冷却，再加热；
(4)方法四：将塞来昔布、卡马西平及添加剂混合，热熔挤出。
本发明首次构建了塞来昔布与卡马西平的药药共晶的制备方法，尤其是采用热熔挤出的制备方法。该法操作简单，重现性好，能够实现连续化制备，适于工业化规模制备，且制备所得的塞来昔布与卡马西平的药药共晶纯度高。
其中，所述塞来昔布与卡马西平的摩尔比优选为1:2～2:1；更优选为1:1。
所述方法一至二采用的溶剂优选自甲醇、乙醇、丙酮、乙酸乙酯、甲苯、四氢呋喃、二氯甲烷、氯仿、乙腈中的一种或多种；更优选为甲苯。优选在室温下将塞来昔布与卡马西平溶解或形成混悬液。
方法一中移除溶剂的方法优选为静置挥发、旋转蒸发；所述方法二优选在30～60℃下移除溶剂；更优选在40℃下移除溶剂。
所述方法三的再加热温度优选为190～210℃，再加热时间优选为0.5～1.5min。
所述方法四采用的添加剂优选自糖醇、聚乙二醇、聚乙二醇1000维生素E琥珀酸酯、聚维酮、泊洛沙姆等的一种或多种；更优选为泊洛沙姆188。
以物料总投入量计，添加剂的用量优选为5～50wt％；更优选为10wt％。
挤出温度优选为100～140℃；更优选为140℃。
作为本发明涉及的第三方面，本发明的药物组合物包含上述塞来昔布-卡马西平共晶以及药学上可接受的载体，优选药物组合物的给药形式未口服或注射。
具体地，上述塞来昔布-卡马西平可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，上述塞来昔布-卡马西平共晶或其药物组合物保留了塞来昔布和卡马西平的生物活性，可作为预防和/或治疗炎症、疼痛或精神类疾病的药物。
具体地，炎症为骨关节炎、风湿性关节炎、类风湿性关节炎或强直性脊柱炎；疼痛为急性疼痛、慢性疼痛、神经性疼痛、痛觉过敏、异位痛、癌痛、纤维肌痛、坐骨神经痛、肩关节冻结、痛经、糖尿病神经病变或糖尿病周围神经病变；精神类疾病为颞叶癫痫、全身强直-阵孪性发作、三叉神经痛、舌咽神经痛、脊髓痨和多发性硬化、糖尿病性周围性神经痛、患肢痛、外伤后神经痛、疱疹后神经痛、躁狂-抑郁症、中枢性部分性尿崩症、精神分裂症、性情感性疾病、与边缘系统功能障碍有关的失控综合征、不宁腿综合征、偏侧面肌痉孪或酒精癖的戒断综合征。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类共晶及其药物组合物在保留了塞来昔布和卡马西平分子结构和生物活性的基础上，其固有溶解速率显著高于塞来昔布并显著低于卡马西平，实现了对两种药物释放的协同调控，尤其是热熔挤出的共晶药物具有更优异的药物溶出-释放性质；
(2)制备方法简便、易操作，制备所得的共晶纯度高，并开发了适于工业化规模的制备方法。
附图说明
图1为实施例1制备的塞来昔布-卡马西平药药共晶的晶体结构图；
图2为实施例1制备的塞来昔布-卡马西平药药共晶的X-射线粉末衍射图谱；
图3为实施例1制备的塞来昔布-卡马西平药药共晶的差示扫描量热图谱；
图4为实施例1制备的塞来昔布-卡马西平药药共晶的热重分析图；
图5为实施例5制备的塞来昔布-卡马西平药药共晶的X-射线粉末衍射图谱；
图6为实施例5制备的塞来昔布-卡马西平药药共晶的差示扫描量热图谱；
图7为塞来昔布、物理混合物中的塞来昔布、共晶中的塞来昔布、挤出物中的塞来昔布的固有溶出曲线；
图8为卡马西平、物理混合物中的卡马西平、共晶中的卡马西平、挤出物中的卡马西平的固有溶出曲线。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
本发明中检测药物共晶结构及性能的仪器如下：
差示扫描量热仪的型号为TA Q2000，具体操作方式为称量3-5mg样品于密封铝坩埚内，以10℃/min的速率升温至200℃，仪器采用金属铟校准，惰性气体高纯氮气(>99.99％)保护，氮气流速50ml/min，分析软件为TA Universal Analysis。
热重分析仪的型号为TA Q500，具体操作方式为将5-15mg样品置于铂金盘中，以20℃/min的速率升温。测试环境由高纯(99.99％)氮气保护，氮气流速40ml/min。
X-射线单晶衍射仪的型号为Bruker Smart ApexⅡ，光源Mo靶，Mo-Kα射线探测器CMOS面探测器，电流电压50kV，30mA，具体操作方式为将单晶放置在载物台，衍射收集数据。然后依次采用SAINT、SADABS程序对数据进行积分还原和吸收校正；接着结合SHELXT2014软件进行单晶结构解析，最后对结构进行精修。Diamond用于晶体结构图的绘制。
X-射线粉末衍射仪的仪器型号为Bruker D8 Advance；靶：Cu-Kα射线管电压：铜钯40KV；电流：40mA；峰位校正：自带的标准样品；采集软件：Diffrac Plus XRDCommander；温度：室温；样品：未进行研磨；2θ角度范围：3-40°；扫描步长：0.02°；扫描速率：1秒/步。
热熔挤出机的型号为Thermo Scientific HAAKE MiniCTW，锥形螺杆直径：4-15mm，螺杆长度：109.4mm。具体操作方式，设置合适的挤出温度和转速，以一定喂料速度喂料，进行挤出。
实施例1：
在室温条件下，将塞来昔布(100mg)与卡马西平(62mg)原料药在10ml甲苯溶液中超声助溶，0.45μm滤头过滤，在室温下缓慢挥发，得到塞来昔布与卡马西平药药共晶。
实施例2：
在室温条件下，将塞来昔布(1.14g)与卡马西平(0.71g)原料药在500ml甲苯溶液中超声助溶，0.45μm滤头过滤，在65℃下旋转蒸发，得到塞来昔布与卡马西平药药共晶。
实施例3：
在室温条件下，称量100mg塞来昔布与62mg卡马西平，往其中加入四氢呋喃溶液0.5ml，形成混悬状态，搅拌1天，在40℃下干燥24h，得到塞来昔布与卡马西平药药共晶。
实施例4：
称量等摩尔的塞来昔布与卡马西平物理混合物，研钵研磨，过筛混合均匀，取300mg混合物于锡箔小船中，将其放置在200℃热台上加热1min，直至熔融完全，用铝块骤冷，得到塞来昔布与卡马西平的共无定形。将该共无定形放置在120℃结晶，即得塞来昔布-卡马西平药药共晶。
实施例5：
称量2.22g塞来昔布、1.38g卡马西平以及0.4g泊洛沙姆188，研钵研磨，过筛混合均匀形成物理混合物。以8g/h的投料速率将混合物投入热熔挤出机，热熔挤出温度设置为140℃，转速30rpm，挤出物即为塞来昔布-卡马西平药药共晶。
实施例6：
称量2.22g塞来昔布、1.38g卡马西平、0.2g聚维酮K30、0.2g聚乙二醇1000维生素E琥珀酸酯，研钵研磨，过筛混合均匀形成物理混合物。以8g/h的投料速率将混合物投入热熔挤出机，热熔挤出温度设置为140℃，转速30rpm，挤出物即为塞来昔布-卡马西平药药共晶。
实施例7：
称量2.22g塞来昔布、1.38g卡马西平、0.2g泊洛沙姆188和0.2g聚乙二醇1000维生素E琥珀酸酯，研钵研磨，过筛混合均匀形成物理混合物。以8g/h的投料速率将混合物投入热熔挤出机，热熔挤出温度设置为140℃，转速30rpm，挤出物即为塞来昔布-卡马西平药药共晶。
实施例中制备的塞来昔布-卡马西平药药共晶通过X-射线粉末衍射、差示扫描量热分析、热重分析等固态化学手段表征后，其结果与实施例1中制备的塞来昔布-卡马西平药药共晶一致。加入添加剂后挤出的共晶由于存在添加剂与共晶之间的相互作用，熔点有略微下降，其DSC图和PXRD图见图5-图6。其中，DSC图中的熔融吸热峰单一且尖锐，表明共晶的纯度高。
实施例8：
对塞来昔布、卡马西平、物理混合物(塞来昔布、卡马西平、泊洛沙姆188)、实施例3所得产物、实施例5所得产物进行固有溶出速率测定。
受试样品来源：实施例中的塞来昔布和卡马西平均从上海阿拉丁生化科技股份公司处购买，泊洛沙姆188从巴斯夫股份公司获取。
实验方法：对塞来昔布(CEL)、卡马西平(CBZ)、物理混合物(PM，塞来昔布、卡马西平、泊洛沙姆188)、实施例3所得产物(CC-CEL、CC-CBZ)、实施例5所得产物(HME-CEL、HME-CBZ)进行研钵研磨处理，控制粒径范围为0.075-0.177毫米，称取待测样品200mg，放入固有溶出模具中，采用1Mpa的压力压制1min。压制完成后，拆除模具使片子的一个面暴露于溶出介质(1％十二烷基硫酸钠水溶液)中，在不同时间点取样，高效液相色谱法测定药物的浓度(10、20、30、40、50、60min)。最终得到塞来昔布、卡马西平、物理混合物中的塞来昔布、物理混合物中的卡马西平、共晶中的塞来昔布、共晶中的卡马西平、挤出物中的塞来昔布、挤出物中的卡马西平共计8条固有溶出曲线。
高效液相色谱测定实验条件：
仪器：岛津LC-20AT高效液相色谱仪
色谱紫外检测仪型号：岛津SPD-20A
色谱四元泵型号：岛津LC-20AT
色谱柱：Agilent Zorbax SB C-18(4.6×250mm,5μm)
流动相：A相：0.1％三氟乙酸水溶液；B相：乙腈；A相与B相的比例为48:52
柱温：30℃
流速：1ml/min
进样量：10μl
检测波长：248nm
实验结果：
原料药、共晶、物理混合物以及挤出物的固有溶出曲线见图7、图8。计算汇总的溶出速率见表1、表2。
表1.塞来昔布固有溶出速率
表2.卡马西平固有溶出速率
结果表明，本发明所制备的塞来昔布-卡马西平药药共晶中的塞来昔布固有溶出速率(9.89±0.01)与原料药塞来昔布(6.88±0.04)相比，溶出速率更快。加入泊洛沙姆188挤出后，挤出物中塞来昔布的溶出速率(21.26±2.55)较物理混合物中的原料药塞来昔布溶出(10.61±0.18)更快。对于卡马西平的固有溶出速率结果(表2)，塞来昔布-卡马西平药药共晶中的卡马西平固有溶出速率(12.26±0.09)与原料药卡马西平(88.04±7.34)相比，溶出速率减慢。加入泊洛沙姆188进行挤出后，挤出物中卡马西平的溶出速率(20.03±0.29)较物理混合物中的原料药塞来昔布溶出(34.78±0.61)更慢。共晶的形成提高了塞来昔布的溶出速率，延缓了卡马西平的溶出，有利于实现两个药物的协同释放，实现联合治疗效果。
Claims (9)
1.一种塞来昔布-卡马西平共晶，其特征在于，所述共晶中塞来昔布与卡马西平的摩尔比为1:1；所述共晶为三斜晶系P1_空间群，晶胞参数为： 轴角α＝88.950(4)°，β＝88.996(4)°，γ＝84.532(5)°。
2.根据权利要求1所述的塞来昔布-卡马西平共晶，其特征在于，以衍射角2θ±0.2°表示，所述共晶在6.18°，7.22°，9.64°，10.44°，12.08°，12.44°，14.28°，14.46°，15.60°，16.34°，17.02°，17.62°，18.20°，18.88°，19.60°，19.86°，20.16°，20.76°，20.90°，21.36°，21.78°，21.96°，22.48°，24.66°处至少具有一个特征衍射峰。
3.根据权利要求1或2所述的塞来昔布-卡马西平共晶，其特征在于，所述共晶在148.6℃±0.2℃处具有特征熔融峰。
4.一种权利要求1～3任一所述的塞来昔布-卡马西平共晶的制备方法，其特征在于，所述制备方法为以下任一方法：
(1)方法一：将塞来昔布与卡马西平溶解于甲苯，过滤后，移除溶剂结晶；
(2)方法二：将塞来昔布与卡马西平在四氢呋喃中形成混悬液，搅拌，移除溶剂；
(3)方法三：将塞来昔布与卡马西平混合，加热熔融，冷却，再加热；
所述的再加热温度为200℃，再加热时间为1min；
(4)方法四：将塞来昔布、卡马西平及添加剂混合，热熔挤出；
所述的添加剂选自糖醇、聚乙二醇、聚乙二醇1000维生素E琥珀酸酯、泊洛沙姆、聚维酮的一种或多种，以物料总投入量计，所述添加剂的用量为5～50wt％；挤出温度为100～140℃。
5.一种药物组合物，其特征在于，包含权利要求1～3任一所述的塞来昔布-卡马西平共晶以及药学上可接受的载体；所述药物组合物的给药形式为口服或注射。
6.一种权利要求1～3任一所述的塞来昔布-卡马西平共晶或权利要求5所述的药物组合物在制备预防和/或治疗炎症、疼痛或精神类疾病药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述炎症为骨关节炎、风湿性关节炎、类风湿性关节炎或强直性脊柱炎。
8.根据权利要求6所述的应用，其特征在于，所述疼痛为急性疼痛、慢性疼痛、神经性疼痛、痛觉过敏、异位痛、癌痛、纤维肌痛、坐骨神经痛、肩关节冻结、痛经、糖尿病神经病变或糖尿病周围神经病变。
9.根据权利要求6所述的应用，其特征在于，所述精神类疾病为颞叶癫痫、全身强直-阵孪性发作、三叉神经痛、舌咽神经痛、脊髓痨和多发性硬化、糖尿病性周围性神经痛、患肢痛、外伤后神经痛、疱疹后神经痛、躁狂-抑郁症、中枢性部分性尿崩症、精神分裂症、性情感性疾病、与边缘系统功能障碍有关的失控综合征、不宁腿综合征、偏侧面肌痉孪或酒精癖的戒断综合征。
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