CN104478979A - 一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法和应用 - Google Patents
一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法和应用 Download PDFInfo
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- RCFZVVHQICKFQW-NGVPHMJWSA-L calcium;[(4ar,6r,7r,7ar)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl] butanoate Chemical compound [Ca+2].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1.C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 RCFZVVHQICKFQW-NGVPHMJWSA-L 0.000 title claims abstract description 97
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Abstract
本发明公开了一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法和应用。该无结晶水二丁酰环磷腺苷钙晶型在使用辐射源为Cu-Kα的粉末X-射线衍射图谱中,在衍射角2θ=12.3°±0.2°、17.6°±0.2、21.4°±0.2°、24.7°±0.2、25.3°±0.2°和27.8°±0.2°处有特征峰。本发明的无结晶水二丁酰环磷腺苷钙晶型纯度高、稳定性好、制备方法简便,而且重现性好,便于工业化推广应用。
Description
技术领域
本发明涉及药物领域,具体涉及一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法和应用。
背景技术
二丁酰环磷腺苷钙为环磷腺苷(cAMP)丁酰化衍生物成钙盐后制得的产品。二磷酸腺苷钙作为蛋白激酶激活剂,可同时激活蛋白激酶A和蛋白激酶C(cAMP仅激活蛋白激酶A)。蛋白激酶是一种别构酶,由两个催化亚基和两个调节亚基组成,催化亚基具有催化蛋白质(或酶)磷酸化作用。故二磷酸腺苷钙可催化人体内最基本的生物化学代谢——氧化磷酸化反应和三羧酸循环,使大多数蛋白质和酶类产生活性,激活人体各种反应,同时产生大量ATP,改善细胞和能量代谢,从而实现其促进神经再生、转化异常细胞、扩张血管、舒张平滑肌、改善心肌缺血等作用。
二丁酰环磷腺苷钙临床上主要用于心绞痛、急性心肌梗死的治疗,亦可用于治疗心肌炎、心源性休克、手术后网膜下出血和银屑病,也可作为辅助抗癌药物用于临床治疗,如白血病等。
但是,二丁酰环磷腺苷钙无定型物原料药或其注射制剂在效期内易发生药物降解而产生相关物质,从而增加药物不良反应,如过敏性休克致心衰死亡、胎盘致畸等。经研究发现,其根本原因在于二丁酰环磷腺苷钙的不稳定性缺陷。
一个化合物的不同晶型被称作“多晶型变体”或“多晶型物”。多晶型物虽有相同的化学结构,但它们在堆积排列和几何排列方面的不同会导致药物稳定性、生物利用度等方面的显著差异,从而直接影响药物质量稳定及其疗效。因此,较为稳定的药物晶型对提高效期内药物临床疗效具有极为重要的价值。
发明内容
本发明所要解决的技术问题即在于克服现有技术中二丁酰环磷腺苷钙无定形物效期内药物质量不稳定的缺陷,提供一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法,以及无结晶水二丁酰环磷腺苷钙晶型物的药物组合物及其制备方法,以及无结晶水二丁酰环磷腺苷钙晶型物在制备治疗心脑血管疾病药物中的应用。本发明的无结晶水二丁酰环磷腺苷钙晶型纯度高、稳定性好、制备方法简便,而且重现性好,便于工业化推广应用。
本发明是通过以下技术方案解决上述技术问题的:
本发明提供了一种无结晶水二丁酰环磷腺苷钙晶型,所述的无结晶水二丁酰环磷腺苷钙晶型在使用辐射源为Cu-Kα的粉末X-射线衍射图谱中,在衍射角2θ=12.3°±0.2°、17.6°±0.2、21.4°±0.2°、24.7°±0.2、25.3°±0.2°和27.8°±0.2°处有特征峰。
其中较佳地,所述的粉末X-射线衍射图谱中,在衍射角2θ=5.3°±0.2°、18.0°±0.2°、33.2°±0.2°、35.2°±0.2°、37.4°±0.2°、39.2°±0.2°、43.4°±0.2°和50.8°±0.2°还有次要峰。
其中较佳地,衍射角为2θ时的特征峰的相对强度如下表所示:
本发明中,所述的无结晶水二丁酰环磷腺苷钙晶型的粉末X-射线衍射图谱如图1所示。
本发明中,所述的无结晶水二丁酰环磷腺苷钙晶型的红外光谱图中,在波数为2974、1751、1704、1619、1465、1256、1105和1022cm-1处有红外吸收特征峰;较佳地,所述的无结晶水二丁酰环磷腺苷钙晶型的红外光谱图如图2所示。
本发明中,所述的无结晶水二丁酰环磷腺苷钙晶型的差示扫描量热法图谱(DSC)中,在120℃~170℃有最大吸收峰;较佳地,在149.4℃有最大吸收峰;更佳地,所述的无结晶水二丁酰环磷腺苷钙晶型的差示扫描量热法图谱如图3所示。
本发明还提供了所述的无结晶水二丁酰环磷腺苷钙晶型的制备方法,其包括下述步骤:将无水二丁酰环磷腺苷钙固体与溶剂混合,加热溶解,活性炭脱色,过滤不溶物,在滤液中加入反溶剂,降温搅拌析晶,即得。
其中,所述的溶剂较佳地为甲醇、乙醇、异丙醇、乙二醇、乙腈、四氢呋喃、二氧六环、乙酸乙酯、二氯甲烷、丙酮和氯仿中的一种或多种。
其中,所述的反溶剂较佳地为正己烷、正戊烷、乙醚、异丙醚、甲基叔丁基醚和甲苯中的一种或多种。
其中,所述的溶剂与所述的无水二丁酰环磷腺苷钙固体的体积质量较佳的比为2~10mL/g。
其中,所述的加热溶解的温度较佳的为25~60℃。
其中,所述的活性炭与所述的无水二丁酰环磷腺苷钙固体的质量比较佳的为(0.01-0.1):1。
本发明中,所述的无水二丁酰环磷腺苷钙固体较佳地为无水二丁酰环磷腺苷钙无定形物。
其中,所述的降温搅拌析晶的温度较佳地为-25~25℃。
其中,所述的反溶剂的加入方式较佳地为滴加,所述的滴加的速率较佳地为0.3~2.0mL/min。
其中,所述的降温搅拌析晶的时间较佳地为1~24h。
本发明又提供了一种药物组合物,所述的药物组合物包含有如上所述的无结晶水二丁酰环磷腺苷钙晶型和药学上可接受的载体。
本发明还又提供了一种如上所述的药物组合物的制备方法,其包括下述步骤:将如上所述的无结晶水二丁酰环磷腺苷钙晶型和药学上可接受的载体混合,即可。
本发明再提供了上述无结晶水二丁酰环磷腺苷钙晶型在制备治疗人类心脑血管疾病药物中的应用。
本发明中:术语“XRPD”是指粉末X-射线衍射;
术语“IR”是指红外光谱法;
术语“DSC”是指差示扫描量热法;
术语“HPLC”是指高效液相色谱法;
术语“1HNMR”是指核磁共振氢谱;
术语“MS”是指质谱法;
术语“反溶剂”是指能与溶剂混溶而不能溶解溶质的溶剂。
本发明提供的无结晶水二丁酰环磷腺苷钙晶型物,通过XRPD图谱、IR图谱和DSC图谱来测定。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
(1)本发明的无结晶水二丁酰环磷腺苷钙晶型纯度高、稳定性好、制备方法简便,而且重现性好,便于工业化推广应用。
(2)本发明对无结晶水二丁酰环磷腺苷钙晶型的数据采集、分析实验研究,有助于开发对水、光、热稳定的药物晶型,这有利于解决本领域长期以来存在的该药物效期内(原料药或注射制剂)储存期间有关物质增加的技术难题,有利于二丁酰环磷腺苷钙产品质量、临床疗效的提升。
附图说明
图1为本发明制备得到的无结晶水二丁酰环磷腺苷钙晶型的粉末X-射线衍射图谱。
图2为本发明制备得到的无结晶水二丁酰环磷腺苷钙晶型的红外光谱图(IR)。
图3为本发明制备得到的无结晶水二丁酰环磷腺苷钙晶型的差示扫描量热法图(DSC)。
图4为无水二丁酰环磷腺苷钙固体的粉末X-射线衍射图(XRPD)。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明提供的无结晶水二丁酰环磷腺苷钙晶型,通过XRPD图谱、IR图谱和DSC图谱来测定。
(1)粉末X-射线衍射法
粉末X-射线衍射使用德国BRUKER-AXS公司的D8ADVANCE X-射线粉末衍射仪,测试条件为:
Cu靶,Kα光源工作电压40KV,工作电流40mA,步长0.02,扫描速度0.3秒/步,扫描角度1.5°~60.0°。
(2)核磁共振氢谱检测方法
核磁共振氢谱检测方法使用Bruker公司AvanceⅢ400MHz,测试方法:将5mg二丁酰环磷腺苷钙原料药或晶型物放入核磁管中用氘水溶解,扫描得到核磁共振氢谱。
(3)质谱检测方法
质谱检测方法采用美国Waters公司ACQUITYTM UPLC&Q-TOF MSPremier,测试方法:
色谱柱为Waters Acquity BEH C18色谱柱(2.1×100mm,1.7μm),串联质谱离子源为电喷雾离子源(ESI),正离子扫描模式检测,毛细管电压为3.0kV,离子源温度为100℃,雾化气温度为350℃,雾化气流量为600.0L·hr-1,碰撞电压分别为4.0eV(MS)和15.0~30.0eV(MS/MS),扫描范围m/z100~1000。
(4)HPLC检测方法
HPLC检测方法采用美国Waters 2695高效液相色谱仪,自动进样器,Waters 2489型UV/Vis检测器,Empower 2数据处理系统。色谱条件:
色谱柱:Diamonsil C18色谱柱(4.6×250mm,5μm);流动相A为50mM甲酸胺(甲酸调节pH至3.0)-乙腈(90︰10),流动相B为乙腈;梯度洗脱条件:0~5min时B从0%到15%,5~10min时B从15%到22%,10~11min时B从22%到25%,11~12min时B从25%到30%,12~13min时B从30%到90%,13~16min时B为90%;流速:1ml·min-1;柱温:30℃;检测波长:273nm;进样量:20μL。此条件下二丁酰环磷酰苷钙主峰的保留时间为11.5min左右。以下实施例均按此法检测HPLC纯度。
下述实施例中的无水二丁酰环磷腺苷钙固体、DBC-Ca·2.3H2O晶体(二丁酰环磷腺苷钙合2.3水)购于上海第一生化药业有限公司。
实施例1 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入甲醇40ml,加热搅拌溶解,加入0.3g活性炭脱色,搅拌15min,滤除不溶物,得到滤液。在滤液中缓慢滴加入100mL乙醚,滴加2h,保持室温,搅拌析晶8h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙晶型物。HPLC纯度95.4%。收率为88%。
实施例2 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入甲醇40ml,加热搅拌溶解,加入0.5g活性炭脱色,搅拌15min,滤除不溶物,得到滤液。在滤液中缓慢滴加入120mL甲苯,滴加2h,保持5-10℃,搅拌析晶5h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙结晶。HPLC纯度95.2%。收率为90%
实施例3 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入甲醇40ml、丙酮10mL,加热搅拌溶解,加入0.3g活性炭脱色,搅拌30min,滤除不溶物,得到滤液。在滤液中缓慢滴加入130mL甲基叔丁基醚,滴加3h,保持0-5℃,搅拌析晶5h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙结晶。HPLC纯度96.2%。收率为89%。
实施例4 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入乙醇35ml,加热搅拌溶解,加入0.5g活性炭脱色,搅拌15min,滤除不溶物,得到滤液。滤液中缓慢滴加入130mL甲基叔丁基醚,滴加3h,保持0-5℃,搅拌析晶5h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙结晶。HPLC纯度95.8%。收率为93%。
实施例5 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入乙醇35ml加热搅拌溶解,加入0.5g活性炭脱色,搅拌30min,滤除不溶物,得到滤液。在滤液中缓慢滴加入120mL正己烷,滴加3h,保持0-5℃,搅拌析晶8h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙结晶。HPLC纯度95.2%。收率为90%。
实施例6 无结晶水二丁酰环磷腺苷钙晶型物制备
称取无水二丁酰环磷腺苷钙固体10g,加入异丙醇60ml加热搅拌溶解,加入0.5g活性炭脱色,搅拌15min,滤除不溶物,得到滤液。在滤液中缓慢滴加入120mL正己烷,滴加2h,保持5-10℃,搅拌析晶8h,析出白色固体,固体经过滤,干燥,得到无结晶水二丁酰环磷腺苷钙结晶。HPLC纯度95.3%。收率为89%。
实施例7 无结晶水二丁酰环磷腺苷钙晶型物X-射线粉末衍射检测
粉末X-射线衍射使用德国BRUKER-AXS公司D8ADVANCE粉末X-射线衍射仪,测试条件为:Cu靶,KαI光源工作电压40KV,工作电流40mA,步长0.02,扫描速度0.3秒/步。扫描角度1.5°~60.0°。实施例1~6制得的无结晶水二丁酰环磷腺苷钙晶型物的粉末X-射线衍射图谱如图1所示,其中,各特征峰的衍射角2θ值、晶面间距以及特征峰的相对强度的参数如下表所示:
实施例8无结晶水二丁酰环磷腺苷钙晶型物红外光谱检测
德国Bruker公司EQUINOX 55红外光谱仪,测试方法:
本发明提供的无结晶水二丁酰环磷腺苷钙结晶用KBr压片并从400至4000cm-1扫描测得的IR图谱,如图2所示,该红外谱图的特征峰位置位于2974、1751、1704、1619、1465、1256、1105、1022cm-1。
实施例9无结晶水二丁酰环磷腺苷钙晶型物差示扫描量热法检测
德国Netzsch公司DSC 204F1差示扫描量热仪,工作条件为:
参比物为Al锅(pan Al),氛围为N2,温度基准物为金属铟,升温速率为10K/min,升温范围0-300℃。
结果显示,该无结晶水二丁酰环磷腺苷钙晶型物中不含有结晶水。
DSC谱图见图3,其在120℃-170℃有最大吸热吸收峰峰值,尤其在149.4℃有最大吸收峰,熔融焓约为26.97J/g。
实施例10无水二丁酰环磷腺苷钙固体X-射线粉末衍射检测
测试条件同实施例7,其X-射线粉末衍射检测图谱如图4所示,结果显示基本为无定形物。
实施例11无水二丁酰环磷腺苷钙固体的核磁共振氢谱(1HNMR)
核磁共振氢谱检测方法使用Bruker公司AvanceⅢ400MHz,测试方法:为将5mg无水二丁酰环磷腺苷钙固体原料药放入核磁管中用氘水溶解,扫描得到核磁共振氢谱。其结果数据为1HNMR(400MHz,D2O):δ=8.58(s,1H);8.37(s,1H);6.29(s,1H);5.64-5.61(d,1H);5.12-5.06(m,1H);4.46-4.37(m,1H);4.28-4.20(m,2H);2.51-2.40(m,4H);1.69-1.53(m,4H);0.93-0.88(t,3H);0.87-0.83(t,3H)。
实施例12无水二丁酰环磷腺苷钙固体的质谱图(MS)
质谱检测方法采用美国Waters公司ACQUITYTM UPLC&Q-TOF MSPremier,测试方法:
色谱柱为Waters Acquity BEH C18色谱柱(2.1×100mm,1.7μm),串联质谱离子源为电喷雾离子源(ESI),正离子扫描模式检测,毛细管电压为3.0kV,离子源温度为100℃,雾化气温度为350℃,雾化气流量为600.0L·hr-1,碰撞电压分别为4.0eV(MS)和15.0~30.0eV(MS/MS),扫描范围m/z100~1000。其检测得到分子离子峰m/z为469.4。
实施例13加速试验及室温长期留样稳定性考察
1、加速试验:将按实施例1制得的无结晶水二丁酰环磷腺苷钙晶型物以及无水二丁酰环磷腺苷钙固体、DBC-Ca·2.3H2O晶体(二丁酰环磷腺苷钙合2.3水)共5个批次样品按原料药包装(用药用低密度聚乙烯袋包装),置于30℃、相对湿度为75±5%的恒温恒湿培养箱中,放置6个月,在试验的第1、2、3、6个月分别取样检测有关物质(HPLC检测方法检测)、含量,并与0月的结果进行比较,结果见表1。
表1 无结晶水二丁酰环磷腺苷钙晶型物和无水固体粉末的湿热加速试验结果
2、长期留样稳定性试验:将按实施例1制得的无结晶水二丁酰环磷腺苷钙晶型物以及无水二丁酰环磷腺苷钙固体、DBC-Ca·2.3H2O晶体(二丁酰环磷腺苷钙合2.3水)共5个批次样品按原料药包装(用药用低密度聚乙烯袋包装),置于16℃、相对湿度为60±5%的恒温恒湿培养箱中,放置12个月,在试验的第3、6、9、12个月分别取样检测有关物质(HPLC检测方法检测)、含量,并与0月的结果进行比较,结果见表2。
表2.无结晶水二丁酰环磷腺苷钙晶型物和无水固体粉末的长期稳定性试验结果
Claims (10)
1.一种无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的无结晶水二丁酰环磷腺苷钙晶型在使用辐射源为Cu-Kα的粉末X-射线衍射图谱中,在衍射角2θ=12.3°±0.2°、17.6°±0.2、21.4°±0.2°、24.7°±0.2、25.3°±0.2°和27.8°±0.2°处有特征峰。
2.如权利要求1所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的粉末X-射线衍射图谱中,在衍射角2θ=5.3°±0.2°、18.0°±0.2°、33.2°±0.2°、35.2°±0.2°、37.4°±0.2°、39.2°±0.2°、43.4°±0.2°和50.8°±0.2°还有次要峰。
3.如权利要求1或2所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的粉末X-射线衍射图谱如图1所示。
4.如权利要求1或2所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的无结晶水二丁酰环磷腺苷钙晶型的红外光谱图中,在波数为2974、1751、1704、1619、1465、1256、1105和1022cm-1处有红外吸收特征峰。
5.如权利要求4所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的无结晶水二丁酰环磷腺苷钙晶型的红外光谱图如图2所示。
6.如权利要求1或2所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的无结晶水二丁酰环磷腺苷钙晶型的差示扫描量热法图谱中,在120℃~170℃有最大吸收峰;较佳地,在149.4℃有最大吸收峰。
7.如权利要求6所述的无结晶水二丁酰环磷腺苷钙晶型,其特征在于,所述的无结晶水二丁酰环磷腺苷钙晶型的差示扫描量热法图谱如图3所示。
8.如权利要求1~7中任一项所述的无结晶水二丁酰环磷腺苷钙晶型的制备方法,其包括下述步骤:将无水二丁酰环磷腺苷钙固体与溶剂混合,加热溶解,活性炭脱色,过滤不溶物,在滤液中加入反溶剂,降温搅拌析晶,即得。
9.如权利要求8所述的制备方法,其特征在于,所述的溶剂为甲醇、乙醇、异丙醇、乙二醇、乙腈、四氢呋喃、二氧六环、乙酸乙酯、二氯甲烷、丙酮和氯仿中的一种或多种;
和/或,所述的反溶剂为正己烷、正戊烷、乙醚、异丙醚、甲基叔丁基醚和甲苯中的一种或多种。
10.如权利要求8所述的制备方法,其特征在于,所述的溶剂与所述的无水二丁酰环磷腺苷钙固体的体积质量比为2~10mL/g;
和/或,所述的加热溶解的温度为25~60℃;
和/或,所述的活性炭与所述的无水二丁酰环磷腺苷钙固体的质量比为(0.01-0.1):1;
和/或,所述的无水二丁酰环磷腺苷钙固体为无水二丁酰环磷腺苷钙无定形物;
和/或,所述的降温搅拌析晶的温度为-25~25℃;
和/或,所述的反溶剂的加入方式为滴加,所述的滴加的速率较佳地为0.3~2.0mL/min;
和/或,所述的降温搅拌析晶的时间为1~24h。
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US15/525,049 US10420787B2 (en) | 2014-12-24 | 2015-03-05 | Crystal-water-free calcium dibutyryladenosine cyclophosphate crystal form and preparation method and application thereof |
PCT/CN2015/073668 WO2016101412A1 (zh) | 2014-12-24 | 2015-03-05 | 一种无结晶水二丁酰环磷腺苷钙晶型及其制备方法和应用 |
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CN105343119A (zh) * | 2015-11-19 | 2016-02-24 | 杭州长典医药科技有限公司 | 环磷酸腺苷或其衍生物在手术后网膜下出血中的应用 |
CN108997430A (zh) * | 2018-07-16 | 2018-12-14 | 南京工业大学 | 一种二丁酰环磷腺苷钙盐的晶体 |
CN114106066A (zh) * | 2021-09-17 | 2022-03-01 | 中国远大集团有限责任公司 | 一种腺苷的晶型及其制备方法 |
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US20180050057A1 (en) | 2018-02-22 |
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