CN114409560A - 阿克他利药物共晶及其制备方法 - Google Patents
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明公开了一种阿克他利药物共晶，所述阿克他利药物共晶以阿克他利为药物活性成分，以吡啶甲酰胺类小分子为共晶形成物，通过分子间氢键形成。并考察了阿克他利药物及其两种共晶在水和模拟十二指肠溶液中的溶解度，发现两种药物共晶均明显改善了阿克他利药物的溶解性，提高了其生物利用度。本发明还公开了阿克他利药物共晶的制备方法，本发明通过药物共晶技术，分别选取烟酰胺和异烟酰胺与阿克他利药物活性成分形成两种阿克他利药物新共晶，显著提高了其溶解性和生物利用度，有利于提高阿克他利的口服吸收效率。本发明工艺简便，成本低廉，有利于进一步生产。
Description
技术领域
本发明属于有机药物共晶领域，尤其涉及阿克他利药物共晶及其制备方法。
背景技术
类风湿性关节炎是一种慢性炎症疾病，常常发病于人体的各个运动关节。其临床症状多表现为晨僵、多关节受累、关节畸形等，对人体危害较大。严重时可导致关节运动功能的丧失，甚至影响心脏、肾脏及呼吸系统受累。
阿克他利(actarit)化学名称为4-乙酰氨基苯乙酸，是由日本三菱化学公司开发的一种口服的免疫调节剂，临床上用于类风湿性关节炎的治疗。对迟缓型过敏反应有抑制作用，可通过降低血清中一氧化氮的浓度，从而改善类风湿关节炎的早期症状。其作用机制是抑制T淋巴细胞的活化与增生。主要通过免疫调节中调节细胞免疫功能来纠正免疫系统的紊乱状态，来对关节炎进行治疗，从而缓解和改善病情。大量临床研究表明，阿克他利对关节炎的治疗率达62.69％。并且具有安全有效、毒性低、药物不良反应小、耐受性好等优点，是一种非常有临床应用前景的抗风湿药物。
然而阿克他利属于BCSII类药物，其溶解性相对较差，导致其口服吸收效果不理想，极大地限制其临床使用。因此，为了提升阿克他利的口服吸收效果及生物利用度，必须解决其溶解性差的问题。
目前，提高口服药物溶解性的方法包括：(1)分子结构改造，在药物分子结构中增加亲水基团。但该法会增加生产成本，并且结构改造后药物活性及药效会发生改变，需要按I类药重新进行审批；(2)药物成盐，通过成盐增加药物的溶解性，但部分药物成盐后不稳定，易分解及潮解等，还有部分药物不含可电离基团，无法通过成盐解决问题；(3)包合技术，通过环糊精包合增加溶解性，但该法只适用于较小的药物，且部分药物与环糊精作用不强无法包合，并且不利于糖尿病人的使用；(4)纳米药物技术，纳米颗粒可以增加溶解性，但部分药物制成纳米颗粒后在胃部发生团聚，重新变成难溶固体，并且工艺复杂，生产成本高；(5)药物共晶技术，药物共晶作为一种新的药物固体形式，是以氢键或其他非共价键结合，具有固体化学计量比的超分子化合物。在改善口服药物溶解性方面优势明显，并且药物共晶具有稳定性好、制备简单、成本低廉等优点得到药物研究界的广泛关注。
CN101244051A中公布了一种使用包合物技术通过制备阿克他利与环糊精及其衍生物包合物来提高阿克他利在水中的溶解性，进而提高阿克他利的生物利用度。该技术主要通过溶剂法、超声法或研磨法实现，主要是通过加入溶媒，将环糊精及其衍生物以及阿克他利制成溶液或糊状物，经过搅拌、超声或研磨一段时间后，再经干燥得到阿克他利与环糊精及其衍生物的包合物。该方法使用的环糊精及其衍生物是环状低聚糖，不利于患有糖尿病的类风湿性关节炎患者服用。
CN1561983A中公布了一种通过制备阿克他利缓释制剂的方法改善阿克他利的溶出速率，进而提高疗效。该缓释片剂主要包括阿克他利、缓释剂、粘合剂、辅料以及润滑剂。该方法所涉及的辅料较多，导致制备复杂、成本增加。
文献(P.Sanphui，V.K.Devi，D.Clara，N.Malviya，S.Ganguly，G.R.Desiraju(2015)Cocrystals of Hydrochlorothiazide：Solubility and Diffusion/PermeabilityEnhancements through Drug-Coformer Interactions，No.12，1615-1622，DOI：10.1021/acs.molpharmaceut.5b00020.)中公布了通过药物共晶的方法来解决氢氯噻嗪水溶性差的问题。制备了氢氯噻嗪与烟酸、烟酰胺、4-氨基苯甲酸、琥珀酰胺以及间苯二酚的五种共晶，并考察了氢氯噻嗪及其五种药物共晶在pH＝7.4的缓冲液中的溶解度。发现氢氯噻嗪与烟酰胺、4-氨基苯甲酸及间苯二酚形成共晶后，溶解度明显增加。而氢氯噻嗪与烟酸及琥珀酰胺形成共晶后，药物共晶的溶解度明显低于氢氯噻嗪药物的溶解度。药物形成共晶后也可能导致其溶解性变差。
上述方法中，包合技术使用的环糊精及其衍生物不利于糖尿病人的使用，其使用范围受限。阿克他利的缓释制剂涉及的辅料多，导致工艺复杂且成本较高。药物共晶是通过共晶形成物的加入来改变药物的结构，进而改变其溶解性。虽然药物共晶在改善药物溶解性方面具有明显的优势，但并不是药物形成共晶后其溶解性就会得到改善，有些药物形成共晶后其溶解性反而有所下降。所以，药物形成共晶后能否改善药物的溶解性依然具有不确定性。
发明内容
发明目的：本发明所要解决的技术问题是提供了两种新的阿克他利药物共晶，形成共晶后显著提高了原料药阿克他利的溶解性及生物利用度。
本发明还要解决的技术问题是提供了一种工艺简便、成本低廉的阿克他利共晶的制备方法。
技术方案：为了解决上述技术问题，本发明提供了一种阿克他利药物共晶，所述阿克他利药物共晶以阿克他利为药物活性成分，以吡啶甲酰胺类小分子为共晶形成物，通过分子间氢键形成。
其中，所述的吡啶甲酰胺类小分子为烟酰胺或异烟酰胺。
其中，所述阿克他利与烟酰胺通过氢键以摩尔比为1∶1形成共晶，所述共晶属于单斜晶系，空间群为P21/n，轴长：
夹角：α/°＝90，β/°＝98.9990(10)，γ/°＝90，
Z＝4。
其中，所述阿克他利-烟酰胺共晶的粉末X射线衍射特征峰出现在2θ＝8.6°，13.7°，15.4°，16.4°，17.3°，19.3°，20.5°，22.6°，24.1°，24.9°，26.2°，26.8°，27.3°，27.6°，28.6°，30.5°，31.3°，33.2°，34.8°，36.9°，38.7°及40.1°。
其中，所述阿克他利与异烟酰胺通过氢键以摩尔比为2∶1形成共晶，所述共晶属于三斜晶系，空间群为
轴长：
夹角：α/°＝94.7850(3)，β/°＝94.0580(3)，γ/°＝93.5820(3)，
Z＝1。
其中，所述阿克他利-异烟酰胺共晶的粉末X射线衍射特征峰出现在2θ＝10.3°，13.8°，18.5°，19.8°，21.4°，23.6°，24.4°，25.5°，27.9°，29.5°，30.3°，35.1°，37.7°，41.4°，41.9°及44.9°。
本发明内容还包括所述的阿克他利药物共晶的制备方法，所述方法为溶剂挥发法，其具体步骤为：按摩尔比1∶0.5～1∶5称取的阿克他利与吡啶甲酰胺类小分子，溶解于一定体积的挥发性有机溶剂中，超声反应30min～120min，溶液经过滤置于15～45℃共晶培养箱中进行恒温培养，5～15天后得阿克他利药物共晶。
其中，所述阿克他利与吡啶甲酰胺类小分子的总质量与挥发性有机溶剂的体积比为1∶10～1∶100g/mL。
其中，所述挥发性有机溶剂为：甲醇、乙醇、正丙醇、异丙醇、丙酮、乙腈、2-丁酮、乙酸乙酯、环己烷、正己烷、氯仿中的任意一种或几种的组合。
其中，当所述挥发性有机溶剂为两种时，其两种有机溶剂的体积比为4∶1～1∶6。
本发明设计制备了具有稳定性好且能够有效改善阿克他利溶解性的药物共晶，对解决阿克他利溶解性差的问题至关重要。同时，也为阿克他利的发展提供一个新方向，并在临床应用中为阿克他利提供更广阔的前景。
有益效果：与现有技术相比，本发明具备以下优点：
(1)本发明通过药物共晶技术，分别选取烟酰胺和异烟酰胺与阿克他利药物活性成分形成两种阿克他利药物新共晶，显著提高了其溶解性和生物利用度，有利于提高阿克他利的口服吸收效率。
(2)本发明提供了一种工艺简便，成本低廉的阿克他利药物共晶的制备方法，有利于进一步生产。
附图说明
图1为阿克他利-烟酰胺药物共晶结构示意图；
图2为阿克他利、烟酰胺及阿克他利-烟酰胺药物共晶的DSC图，图中A/I表示阿克他利-烟酰胺共晶；
图3为阿克他利、烟酰胺及阿克他利-烟酰胺药物共晶的PXRD图，图中A/I表示阿克他利-烟酰胺共晶；
图4为阿克他利-异烟酰胺药物共晶结构示意图；
图5为阿克他利、异烟酰胺及阿克他利-异烟酰胺药物共晶的DSC图，图中A/N表示阿克他利-异烟酰胺共晶；
图6为阿克他利、异烟酰胺及阿克他利-异烟酰胺药物共晶的PXRD图，图中A/N表示阿克他利-异烟酰胺共晶；
图7为阿克他利、阿克他利-烟酰胺药物共晶及阿克他利-异烟酰胺药物共晶在水中的溶解度对比图；
图8为阿克他利、阿克他利-烟酰胺药物共晶及阿克他利-异烟酰胺药物共晶在模拟十二指肠中的溶解度对比图。
具体实施方式
下面结合附图和实施例对本发明作进一步的说明。
实施例1
称取193.2mg的阿克他利和122.1mg的烟酰胺，溶于10mL体积比为1∶1的丙酮和环己烷的混合溶剂，超声反应50min，经过滤后，置于35℃的恒温培养箱中恒温培养，8天后，得到阿克他利-烟酰胺药物共晶。使用SXRD对该晶体进行表征并解析，所得阿克他利-烟酰胺晶体结构如图1所示，其晶体结构属于单斜晶系，空间群为P21/n，轴长：
夹角：α/°＝90，β/°＝98.9990(10)，γ/°＝90，
Z＝4。
实施例2
称取193.2mg的阿克他利和183.2mg的烟酰胺，溶于20mL体积比为2∶1的乙腈和氯仿的混合溶剂，超声反应70min，经过滤后，置于30℃的恒温培养箱中恒温培养，10天后，得到阿克他利-烟酰胺药物共晶。使用差示扫描量热法对该药物共晶进行表征，阿克他利-烟酰胺共晶在115.96℃处有吸收峰，DSC图如图2所示。
实施例3
称取96.6mg的阿克他利和122.1mg的烟酰胺，溶于15mL体积比为1∶6的甲醇和氯仿的混合溶剂，超声反应40min，经过滤后，置于40℃的恒温培养箱中恒温培养，14天后，得到阿克他利-烟酰胺药物共晶。使用PXRD对所获晶体进行表征，阿克他利-烟酰胺共晶在2θ＝8.6°，13.7°，15.4°，16.4°，17.3°，19.3°，20.5°，22.6°，24.1°，24.9°，26.2°，26.8°，27.3°，27.6°，28.6°，30.5°，31.3°，33.2°，34.8°，36.9°，38.7°及40.1°处有特征峰，特征曲线如图3所示。
实施例4
称取193.2mg的阿克他利和61.1mg的异烟酰胺，溶于20mL体积比为3∶1的乙腈和氯仿的混合溶剂，超声反应60min，经过滤后，置于40℃的恒温培养箱中恒温培养，14天后，得到阿克他利-异烟酰胺药物共晶。使用SXRD对该晶体进行表征并解析，所得阿克他利-异烟酰胺晶体结构如图4所示，其晶体结构属于三斜晶系，空间群为
轴长：
夹角：α/°＝94.7850(3)，β/°＝94.0580(3)，γ/°＝93.5820(3)，
Z＝1。
实施例5
称取48.3mg的阿克他利和152.6mg的异烟酰胺，溶于10mL体积比为4∶1的甲醇和环己烷的混合溶剂，超声反应100min，经过滤后，置于30℃的恒温培养箱中恒温培养，7天后，得到阿克他利-异烟酰胺药物共晶。使用差示扫描量热法对该药物共晶进行表征，阿克他利-异烟酰胺共晶在148.22℃处有吸收峰，DSC图如图5所示。
实施例6
称取193.2mg的阿克他利和122.1mg的异烟酰胺，溶于15mL体积比为2∶1的丙酮和环己烷的混合溶剂，超声反应120min，经过滤后，置于25℃的恒温培养箱中恒温培养，10天后，得到阿克他利-异烟酰胺药物共晶。使用PXRD对所获晶体进行表征，阿克他利-异烟酰胺共晶在2θ＝10.3°，13.8°，18.5°，19.8°，21.4°，23.6°，24.4°，25.5°，27.9°，29.5°，30.3°，35.1°，37.7°，41.4°，41.9°及44.9°处有特征峰，特征曲线如图6所示。
实施例7
称取过量的阿克他利、实施例1制备的阿克他利-烟酰胺共晶及实施例4制备的阿克他利-异烟酰胺共晶各200mg分别溶解于3mL的水和3mL的模拟十二指肠液中，考察其溶解性，其结果如图7和图8所示，在水和模拟十二指肠液中，阿克他利-烟酰胺共晶及阿克他利-异烟酰胺共晶的溶解性明显优于阿克他利。
综合上述各项的结果，成功地制备出阿克他利-烟酰胺及阿克他利-异烟酰胺共晶，并能够有效的提高阿克他利药物的溶解性。
Claims (10)
1.一种阿克他利药物共晶，其特征在于，所述阿克他利药物共晶以阿克他利为药物活性成分，以吡啶甲酰胺类小分子为共晶形成物，通过分子间氢键形成。
2.根据权利要求1所述的阿克他利药物共晶，其特征在于，所述的吡啶甲酰胺类小分子为烟酰胺或异烟酰胺。
3.根据权利要求2所述的阿克他利药物共晶，其特征在于，所述阿克他利与烟酰胺通过氢键以摩尔比为1:1形成共晶，所述共晶属于单斜晶系，空间群为P21/n，轴长：a/Å=11.4827(4)，b/Å=7.7170(3)，c/Å=17.0050(6)，夹角：α/°=90，β/°=98.9990(10)，γ/°=90，Volume/Å3=1488.30(9)，Z=4。
4.根据权利要求2所述的阿克他利药物共晶，其特征在于，所述阿克他利-烟酰胺共晶的粉末X射线衍射特征峰出现在2θ=8.6°，13.7°，15.4°，16.4°，17.3°，19.3°，20.5°，22.6°，24.1°，24.9°，26.2°，26.8°，27.3°，27.6°，28.6°，30.5°，31.3°，33.2°，34.8°，36.9°，38.7°及40.1°。
5.根据权利要求2所述的阿克他利药物共晶，其特征在于，所述阿克他利与异烟酰胺通
过氢键以摩尔比为2:1形成共晶，所述共晶属于三斜晶系，空间群为P
，轴长：a/Å= 4.9256
(2)，b/Å= 4.9918(2)，c/Å= 25.6686(9)，夹角：α/°= 94.7850(3)，β/°= 94.0580(3)，γ/°=
93.5820(3)，Volume/Å3= 625.87(4) ，Z=1。
6.根据权利要求2所述的阿克他利药物共晶，其特征在于，所述阿克他利-异烟酰胺共晶的粉末X射线衍射特征峰出现在2θ=10.3°，13.8°，18.5°，19.8°，21.4°，23.6°，24.4°，25.5°，27.9°，29.5°，30.3°，35.1°，37.7°，41.4°，41.9°及44.9°。
7.权利要求1~6任一所述的阿克他利药物共晶的制备方法，其特征在于，所述方法为溶剂挥发法，其具体步骤为：按摩尔比1:0.5~1:5称取的阿克他利与吡啶甲酰胺类小分子，溶解于挥发性有机溶剂中，超声反应30min~120min，溶液经过滤置于15~45℃共晶培养箱中进行恒温培养，5~15天后得阿克他利药物共晶。
8.根据权利要求7所述的阿克他利药物共晶的制备方法，其特征在于，所述阿克他利与吡啶甲酰胺类小分子的总质量与溶剂的体积比为1:10~1:100g/mL。
9.根据权利要求7所述的阿克他利药物共晶的制备方法，其特征在于，所述挥发性有机溶剂为：甲醇、乙醇、正丙醇、异丙醇、丙酮、乙腈、2-丁酮、乙酸乙酯、环己烷、正己烷、氯仿中的任意一种或几种的组合。
10.根据权利要求9所述的阿克他利药物共晶的制备方法，其特征在于，当所述挥发性有机溶剂为两种时，其体积比为4:1~1:6。
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