CN105175263A - 普伐他汀钠药物共晶及其制备方法和用途 - Google Patents

普伐他汀钠药物共晶及其制备方法和用途 Download PDF

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CN105175263A
CN105175263A CN201510628045.8A CN201510628045A CN105175263A CN 105175263 A CN105175263 A CN 105175263A CN 201510628045 A CN201510628045 A CN 201510628045A CN 105175263 A CN105175263 A CN 105175263A
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pravastatin sodium
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张娜
武香香
吕扬
何兰
杨化新
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Abstract

本发明属于有机药物共晶技术领域，具体涉及一种普伐他汀钠药物共晶及其制备方法和用途。所述普伐他汀钠的药物共晶包括共晶形成物与活性组分普伐他汀钠，其中，所述共晶形成物为氨基酸、脲类、金刚烷衍生物或其它小分子化合物。结果发现形成共晶前后，药品的吸湿性能发生了显著的变化，如赖氨酸和尿素的共晶引湿性增加，金刚烷胺盐酸盐形成的共晶在70％湿度以下基本不引湿。

Description

普伐他汀钠药物共晶及其制备方法和用途
技术领域
本发明属于有机药物共晶技术领域，具体涉及一种普伐他汀钠药物共晶及其制备方法和用途。
背景技术
普伐他汀钠，英文名为PravastatinSodium，化学名称为{1S-[1α(βS*，δS*)，2α，6α，8β(R*)，8aα]}-1,2,6,7,8,8a-六氢-β,δ,6-三羟基-2-甲基-8-(2-甲基-1-氧代丁氧基)-1-萘庚酸单钠盐，是3-羟基3-甲基戊二酰辅酶A还原酶(HMG-CoA还原酶)的竞争性抑制剂，是一种高效调脂药，并能显著减缓动脉粥样硬化进程，可用于高脂血症、家族性高胆固醇血症。不过，普伐他汀钠属于生物药剂学分类系统(BCS)中的三类药物，作为固体口服剂型仍存在很多的挑战，如生物利用度低(17％)、高水溶性、低渗透性，胃酸性环境中不稳定，强引湿性，多晶型(已有至少16种晶型报道)，且结晶过程不易控制等等。因此获得更高活性，质量易控，更好稳定性的药品化合物吸引了各国药品公司的关注。
药物共晶，或称多组分晶体，是一类在常温下均为固体的共晶形成物(cocrystalformer,CCF)和药物活性成分(activepharmaeeuticalingredient,API)，通过氢键自组装，或者带有饱和性和方向性的非共价键(如芳烃或苯环的范德华力，π-π共轭作用和卤键)组装形成的一种新型结构，各组分之间存在固定的化学计量比。药物共晶结构中的氢键或其它非共价键的形成不会发生改变分子本身的性质，也不会破坏分子内部固有的共价键。选择合适的CCF与药物活性成分API组成共晶，往往可以很大程度上改变药物的各种理化性质及药学性质，如熔点，溶解度，生物利用度，引湿性，化学稳定性等。共晶能够使药物的固体形态更丰富，尤其是对于无定形、非解离或pKa较低的活性药物成分，共晶是改变药物固体形态的一种重要手段。近年来共晶技术已成为药物研发的新途径，药物共晶的合成与性质使其在药物学、生物医学领域显示出了诱人的应用前景。超分子合成子和合成子竞争是共晶设计的基础。尽管合成子方法很成功，但是还不能准确预测哪些可以形成共晶，对于是否形成共晶还有其他未知的因素影响。
发明内容
本发明的目的是提供普伐他汀钠药物共晶。
本发明的再一目的是提供普伐他汀钠药物共晶的制备方法。
本发明的目的是提供上述普伐他汀钠药物共晶的用途。
根据本发明的普伐他汀钠药物共晶，包括各种共晶形成物(cocrystalformer,CCF)氨基酸、脲类、亲脂性的金刚烷衍生物与普伐他汀钠形成的共晶混合物。
其中，所选共晶形成物(cocrystalformer,CCF)如下所示：
氨基酸：组氨酸、赖氨酸、精氨酸、苏氨酸、异亮氨酸、丝氨酸、蛋氨酸、缬氨酸、苯丙氨酸、天冬氨酸；脲类：硫脲、尿素；金刚烷衍生物：1-金刚烷胺盐酸盐、1-金刚烷甲酸；其它小分子：糖精、苹果酸。
根据本发明的普伐他汀钠药物共晶制备方法包括以下步骤：
将等摩尔量的普伐他汀钠与CCF分子置于玛瑙研钵中，向其中加入甲醇或水，然后进行研磨，在研磨的过程中再不断补加甲醇或水，研磨30min，取出，置于真空干燥箱中在60℃干燥，得到普伐他汀钠药物共晶。
为证实共晶化合物的形成，将共晶混合物(GM)和物理混合物(PM，将等摩尔量的普伐他汀钠与CCF分子混合即得)进行了傅利叶红外光谱(FT-IR)对照，主要考察与-OH，-NH，-C＝O对应的伸缩振动频率在2500～3400,1500～1750cm-1范围内的变化，结果发现赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、金刚烷胺的共晶混合物(GM)和物理混合物(PM)在以上波长范围内有较明显的差异，初步预示了共晶化合物的形成。
为对以上结论做进一步证实，还对以上体系的共晶混合物(GM)和物理混合物(PM)做了粉末衍射(PXRD)对照。共晶混合物(GM)的差热谱图(DSC)也显示出与物理混合物(PM)和无定形普伐他汀钠完全不同的热力学行为。如普伐他汀钠/金刚烷胺共晶(GM)只在195.28℃出现一个尖锐的吸热峰，对应为共晶的熔点，而无定形的普伐他汀钠在达到熔点173.17℃前，在96.46，107.46℃左右出现较宽的两个吸热峰，143.13和145.65℃左右分别出现一个吸热峰和放热峰。
粉末引湿后可能发生固相转变，如无水晶体转变成水合晶体，无定形转变成晶体及多晶型转变，继而可能影响API的体内生物利用度。本发明形成普伐他汀钠的共晶物的意义也在于降低其引湿性，，为证实形成共晶前后药物引湿性的变化，将制备的共晶样品和普伐他汀钠分别置于SMSDVS-2仪器中放置15小时，调节相对湿度水平为RH20％～80％～20％，结果发现形成共晶前后，药品的吸湿性能发生了显著的变化，如赖氨酸和尿素的共晶引湿性增加，金刚烷胺盐酸盐形成的共晶在70％湿度以下基本不引湿。
实验数据表明，以上共晶形成物CCF中，水杨酸、对羟基苯甲酸甲酯、龙胆酸、糖精、1-金刚烷甲酸均形成了低共熔混合物，不适宜制备固体制剂；而赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、金刚烷胺均形成了特征明显的共晶化合物。
为解决现有普伐他汀钠制剂的缺陷，本发明利用晶体工程策略，结合普伐他汀钠结构中存在的羟基和羰基的给受体基团的特点，用溶剂辅助研磨法，能够促进形成共晶的动力学优势，提高固体分子间的移动性，加快共晶生成速率。合成共晶的过程中不需要考虑活性药物成分和配体的溶解度问题，同时避免了单一组分溶剂化物生成的情况，而且液体助导研磨溶剂使用量少，实验制备时间短，是一种绿色的制备方法。
附图说明
图1-1为普伐他汀钠/赖氨酸共晶(GM)和物理混合物(PM)的IR谱图；
图1-2为普伐他汀钠/赖氨酸共晶(GM)和物理混合物(PM)的PXRD谱图；
图1-3为普伐他汀钠/赖氨酸共晶(GM)的DVS图；
图2-1为普伐他汀钠/苯丙氨酸共晶(GM)和物理混合物(PM)的IR谱图；
图2-2为普伐他汀钠/苯丙氨酸共晶(GM)和物理混合物(PM)的PXRD谱图；
图3-1为普伐他汀钠/苏氨酸共晶(GM)和物理混合物(PM)的IR谱图；
图3-2为普伐他汀钠/苏氨酸共晶(GM)和物理混合物(PM)的PXRD谱图；
图4-1为普伐他汀钠/尿素共晶(GM)和物理混合物(PM)的IR谱图；
图4-2为普伐他汀钠/尿素共晶(GM)和物理混合物(PM)的PXRD谱图；
图4-3为普伐他汀钠/尿素共晶(GM)的DVS图；
图5-1为普伐他汀钠/硫脲共晶(GM)和物理混合物(PM)的IR谱图；
图5-2为普伐他汀钠/硫脲共晶(GM)和物理混合物(PM)的PXRD谱图；
图5-3为普伐他汀钠/硫脲共晶(GM)的DVS图；
图6-1为普伐他汀钠/金刚烷胺共晶(GM)和物理混合物(PM)的IR谱图；
图6-2为普伐他汀钠/金刚烷胺共晶(GM)和物理混合物(PM)的PXRD谱图；
图6-3为普伐他汀钠/金刚烷胺共晶(GM)和物理混合物(PM)的DSC曲线；
图6-4为普伐他汀钠/金刚烷胺共晶(GM)的DVS图；
图7为普伐他汀钠的DSC曲线。
具体实施方式
以下结合实施例对本发明的具体实施方式作进一步详细说明。本发明所涉及的检测仪器如下：
傅利叶红外光谱(FT-IR)：PerkinElmerSpectrum100Spectrometer，常温，KBr压片，波长4,000～450cm-1.
粉末衍射仪(PXRD)：RigakuD/max-2550，CuKα辐射，石墨单色器.
热重分析仪：MettlerToledoTGA/DSC1/LF/850，温度30-300℃，升温速率10K/min，保护氮气50.0mL/min.
差示扫描量热计(DSC)：MettlerToledoDSC1/500/367，温度30-300℃，升温速率10K/min，保护氮气50.0mL/min.
动态水分吸附测定仪(DynamicVapourSorptionDVS)：SMSDVS-2
实施例1
将等摩尔量的普伐他汀钠与以下CCF分子置于玛瑙研钵中，向其中加入甲醇或水，然后进行研磨，在研磨的过程中再不断补加甲醇或水，研磨30min，取出，置于真空干燥箱中在60℃干燥，得到普伐他汀钠药物共晶。
CCF分子：氨基酸：组氨酸、赖氨酸、精氨酸、苏氨酸、异亮氨酸、丝氨酸、蛋氨酸、缬氨酸、苯丙氨酸、天冬氨酸；脲类：硫脲、尿素；金刚烷衍生物：1-金刚烷胺盐酸盐、1-金刚烷甲酸；其它小分子：糖精、苹果酸。
为证实共晶化合物的形成，将共晶混合物(GM)和物理混合物(PM，将等摩尔量的普伐他汀钠与CCF分子混合即得)进行了傅利叶红外光谱(FT-IR)对照，主要考察与-OH，-NH，-C＝O对应的伸缩振动频率在2500～3400,1500～1750cm-1范围内的变化，结果发现赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、金刚烷胺的共晶混合物(GM)和物理混合物(PM)在以上波长范围内有较明显的差异，初步预示了共晶化合物的形成。
为对以上结论做进一步证实，还对以上体系的共晶混合物(GM)和物理混合物(PM)做了粉末衍射(PXRD)对照，得到各体系的共晶特征峰如下：
普伐他汀钠/赖氨酸共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为17.940,19.419,19.760,25.660,20.362,22.080,17.279,16.760,27.160,23.840.
普伐他汀钠/赖氨酸物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为17.160,20.000,18.040,11.800,8.680,10.161,20.480,22.680,4.040,24.341.
普伐他汀钠/苯丙氨酸共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为22.640,5.621,20.519,17.780,16.498,17.298,18.300,19.481,34.280,28.440.
普伐他汀钠/苯丙氨酸物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为5.720,17.040,22.759,17.840,22.421,19.980,16.700,16.220,18.619,4.019.
普伐他汀钠/苏氨酸共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为20.580,22.770,16.440,29.559,21.641,18.320,17.241,23.880,15.920,35.059.
普伐他汀钠/苏氨酸物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为26.161,17.160,13.159,12.999,16.080,19.900,3.959,28.641,22.440,10.060.
普伐他汀钠/尿素共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为22.060,16.880,6.120,9.660,19.339,24.421,3.540,29.140,35.341,31.500.
普伐他汀钠/尿素物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为17.060,21.660,35.480,19.820,16.081,22.299,11.640,10.000,3.900,7.199.
普伐他汀钠/硫脲共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为19.600,20.580,17.180,17.779,28.720,28.201,18.780,25.299,18.301,22.563.
普伐他汀钠/硫脲物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为19.899,23.220,17.100,17.280,16.199,16.001,10.080,3.922,8.562,7.240.
普伐他汀钠/金刚烷胺共晶(GM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为15.200,31.599,18.780,17.400,20.740,45.300,9.800,12.380,17.860,19.860.
普伐他汀钠/金刚烷胺物理混合物(PM)的的X射线衍射图谱，以衍射角2θ°±0.1表示为18.240,16.040,17.240,18.660,27.460,20.080,24.320,11.860,14.220,21.560.
共晶混合物(GM)的差热谱图(DSC)也显示出与物理混合物(PM)和无定形普伐他汀钠完全不同的热力学行为。如普伐他汀钠/金刚烷胺共晶(GM)只在195.28℃出现一个尖锐的吸热峰，对应为共晶的熔点，而无定形的普伐他汀钠在达到熔点173.17℃前，在96.46，107.46℃左右出现较宽的两个吸热峰，143.13和145.65℃左右分别出现一个吸热峰和放热峰。
实验数据表明，以上共晶形成物CCF中，水杨酸、对羟基苯甲酸甲酯、龙胆酸、糖精、1-金刚烷甲酸均形成了低共熔混合物，不适宜制备固体制剂；而赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、金刚烷胺均形成了特征明显的共晶化合物。
药物引湿性测定
粉末引湿后可能发生固相转变，如无水晶体转变成水合晶体，无定形转变成晶体及多晶型转变，继而可能影响API的体内生物利用度。本发明形成普伐他汀钠的共晶物的意义也在于降低其引湿性，为证实形成共晶前后药物引湿性的变化，将制备的共晶样品和普伐他汀钠分别置于SMSDVS-2仪器中放置15小时，调节相对湿度水平为RH20％～80％～20％，结果发现形成共晶前后，药品的吸湿性能发生了显著的变化，如赖氨酸和尿素的共晶引湿性增加，金刚烷胺盐酸盐形成的共晶在70％湿度以下基本不引湿。

Claims (5)

1.一种普伐他汀钠的药物共晶，其特征在于，所述普伐他汀钠的药物共晶包括共晶形成物与活性组分普伐他汀钠，其中，所述共晶形成物为氨基酸、脲类、金刚烷衍生物或其它小分子化合物。
2.根据权利要求1所述的普伐他汀钠的药物共晶，其特征在于，所述共晶形成物为赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、或金刚烷胺。
3.一种制备权利要求1所述的普伐他汀钠的药物共晶的方法，其特征在于，将等摩尔量的普伐他汀钠与共晶形成物混合，加入甲醇或水，然后进行研磨，在研磨的过程中再不断补加甲醇或水，研磨30min，取出，置于真空干燥箱中在60℃干燥，得到普伐他汀钠药物共晶。
4.根据权利要求3所述的方法，其特征在于，所述共晶形成物为赖氨酸、苯丙氨酸、苏氨酸、尿素、硫脲、或金刚烷胺。
5.权利要求1所述的普伐他汀钠的药物共晶在制备用于调脂、减缓动脉粥样硬化进程、治疗高脂血症、或家族性高胆固醇血症的药物中的应用。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107188799A (zh) * 2017-05-09 2017-09-22 中国食品药品检定研究院 芬布芬共晶及其制备方法与应用
CN110279865A (zh) * 2019-08-12 2019-09-27 黄泳华 一种具有协同抑菌作用的共晶复合物
CN112638866A (zh) * 2018-07-06 2021-04-09 艾科西斯有限责任公司 索拉非尼衍生物的共晶体及其制备方法
CN115448897A (zh) * 2022-09-28 2022-12-09 中国食品药品检定研究院 一种抗坏血酸药物共晶及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1692907A (zh) * 2004-05-08 2005-11-09 鲁南制药集团股份有限公司 治疗高血脂症的组合物
WO2006033287A1 (ja) * 2004-09-21 2006-03-30 Sankyo Company, Limited ＨＭＧ－ＣｏＡリダクターゼ阻害剤とグルタチオンを含有する医薬組成物。
CN1774443A (zh) * 2003-04-15 2006-05-17 生命健康科学有限公司 仲醇磷酸盐
JP2012176919A (ja) * 2011-02-28 2012-09-13 Kowa Co 医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1774443A (zh) * 2003-04-15 2006-05-17 生命健康科学有限公司 仲醇磷酸盐
CN1692907A (zh) * 2004-05-08 2005-11-09 鲁南制药集团股份有限公司 治疗高血脂症的组合物
WO2006033287A1 (ja) * 2004-09-21 2006-03-30 Sankyo Company, Limited ＨＭＧ－ＣｏＡリダクターゼ阻害剤とグルタチオンを含有する医薬組成物。
JP2012176919A (ja) * 2011-02-28 2012-09-13 Kowa Co 医薬組成物

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107188799A (zh) * 2017-05-09 2017-09-22 中国食品药品检定研究院 芬布芬共晶及其制备方法与应用
CN107188799B (zh) * 2017-05-09 2020-10-30 中国食品药品检定研究院 芬布芬共晶及其制备方法与应用
CN112638866A (zh) * 2018-07-06 2021-04-09 艾科西斯有限责任公司 索拉非尼衍生物的共晶体及其制备方法
CN112638866B (zh) * 2018-07-06 2023-06-09 艾科西斯有限责任公司 索拉非尼衍生物的共晶体及其制备方法
US11987542B2 (en) 2018-07-06 2024-05-21 Eicosis, Llc Co-crystal of sorafenib derivatives and process for preparation thereof
CN110279865A (zh) * 2019-08-12 2019-09-27 黄泳华 一种具有协同抑菌作用的共晶复合物
CN115448897A (zh) * 2022-09-28 2022-12-09 中国食品药品检定研究院 一种抗坏血酸药物共晶及其制备方法

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