CN102219783A - 盐酸维拉佐酮及其组合物 - Google Patents
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Abstract
本发明涉及维拉佐酮（vilazodone）二盐酸盐的晶型及其制备方法，本发明还涉及含有上述晶型的维拉佐酮的药物组合物及该晶型用于制造治疗忧郁症药物中的应用。
Description
技术领域
本发明涉及含有维拉佐酮（vilazodone）二盐酸盐晶型的药物组合物、制备方法及该晶型用于制造治疗忧郁症的药物中的应用。
背景技术
抑郁症是一种因脑生化改变所致的疾病，体征和症状包括：情绪低落、对寻常活动丧失兴趣，体重或食欲显著变化，失眠或过度睡眠(嗜睡)，坐立不安/调步(精神运动性激越)，疲乏增加，有罪感或自卑感，思维缓慢或注意力不集中，严重者有自伤和自杀冲动。严重影响人们的工作，睡眠，学习，饮食和享受愉快活动的能力。
中枢去甲肾上腺素(NE)、5一羟色胺(5一HT)、多巴胺(DA)等单胺类神经递质含量过低及其受体功能低下等都被认为是引起抑郁症的原因。最初对抑郁症的治疗是采用电刺激休克疗法，但多次使用常会失去疗效。当前用于抑郁症治疗的药物主要有3类，一类是三环类抗抑郁药(tricyclic antidepressant，TCA)，它可提高脑中NE和5-HT的浓度，已成为抑郁症的标准治疗药物，但它起效慢，伴有严重不良反应，如心脏毒性；另一类抗抑郁药为单胺氧化酶抑制剂(monoamine oxidase inhibitor，MAOI)，它能延缓大脑中NE和5一HT的降解，延长这些递质的作用时间；20世纪80年代，又开发出新一类抗抓郁药— 选择性5一HT再摄取抑制剂(selective serotoninreuptake inhibitor，SSRI)，它可抑制突触前膜对5-HT的再摄取，增加突触间隙5一HT的浓度，提高突触后膜5-HT1A受体的兴奋性，产生抗抑郁作用，而它并不影响其他神经递质受体，因而较安全。但是SSRI在治疗严重抑郁症时疗效不及TCA，而且，由于它非选择地刺激5一HT受体的各种亚型，所以会产生一些相关的不良反应。在同一年代，研究人员发现丁螺环酮对5-HT1A受体有很高的亲和性，这个发现推动了选择性5-HT1A受体激动剂类抗抑郁药的发展。
盐酸维拉佐酮（vilazodone hydrochloride）
2-benzofurancarboxamide,5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1)。分子式为C26H27N5O2.HCl，其分子量为477.99。化学结构式为：
本品既是SSRI也是5-HT1A的部分激动剂，在激动5-HT1A受体的同时可快速提高5-HT细胞外浓度，发挥快速抗抑郁作用。
盐酸维拉佐酮有多种晶型：Journal of Medicinal Chemistry,2004,
47(19):4684-4692,报道了一种固体形态，m.p.277-279 °C；US5532241（实例4）公开了一种固体形态，m.p.269-272°C；WO2002102794公开了盐酸维拉佐酮5种晶型，盐酸维拉佐酮3种水合物的晶型，盐酸维拉佐酮6种溶剂化物的晶型，盐酸维拉佐酮1种无定型形态，维拉佐酮二盐酸盐1种晶型等等。
本发明人在研究过程中，发现维拉佐酮二盐酸盐也存在多晶现象，发现了其它四种晶型，不同于上述专利中公开的那种晶型，惊奇的是，其中一种晶型不同于另外三种晶型，具有优良的特性，该晶型溶解度大，这对药物发挥疗效极其重要，还具有纯度高，稳定性好，在工业生产上具有优越性，适合制剂工艺过程和长期储存。
发明内容
本发明的一个目的，公开了一种维拉佐酮二盐酸盐的新晶型。
本发明的另一个目的，公开了维拉佐酮二盐酸盐新晶型的制备方法。
本发明的又一个目的，公开了包含维拉佐酮二盐酸盐新晶型的药物组合物。
本发明还公开了维拉佐酮二盐酸盐新晶型在制造治疗忧郁症药物中的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明提供了一种维拉佐酮二盐酸盐的新晶型，该晶型X射线粉末衍射特征吸收峰（2θ）和D值如下，误差为±0.2，见图1。
| 峰数 | 衍射角（2θ） | D值 | I/I0 |
| 1 | 11.140 | 7.9360 | 100 |
| 2 | 12.680 | 6.9754 | 8 |
| 3 | 14.500 | 6.1037 | 2 |
| 4 | 15.140 | 5.8471 | 1 |
| 5 | 16.580 | 5.3424 | 1 |
| 6 | 17.380 | 5.0982 | 4 |
| 7 | 17.900 | 4.9513 | 2 |
| 8 | 19.660 | 4.5118 | 3 |
| 9 | 21.820 | 4.0698 | 26 |
| 10 | 22.380 | 3.9692 | 83 |
| 11 | 23.960 | 3.7109 | 1 |
| 12 | 24.660 | 3.6072 | 4 |
| 13 | 25.460 | 3.4956 | 48 |
| 14 | 26.220 | 3.3960 | 8 |
| 15 | 26.820 | 3.3214 | 2 |
| 16 | 27.420 | 3.2500 | 2 |
| 17 | 27.860 | 3.1997 | 4 |
| 18 | 28.640 | 3.1143 | 2 |
| 19 | 30.580 | 2.9210 | 1 |
| 20 | 31.920 | 2.8014 | 5 |
| 21 | 32.540 | 2.7494 | 5 |
| 22 | 33.820 | 2.6482 | 6 |
| 23 | 34.240 | 2.6167 | 2 |
| 24 | 34.860 | 2.5715 | 1 |
| 25 | 37.600 | 2.3902 | 1 |
| 26 | 37.840 | 2.3756 | 1 |
| 27 | 40.200 | 2.2414 | 3 |
| 28 | 43.900 | 2.0607 | 4 |
| 29 | 44.560 | 2.0317 | 2 |
| 30 | 45.080 | 2.0095 | 1 |
| 31 | 45.640 | 1.9861 | 4 |
| 32 | 47.480 | 1.9133 | 5 |
本发明中2θ值的测定使用光源，精度为±0.2°，因此代表上述所取的值允许有一定合理的误差范围，其误差范围为±0.2°。
熔点测定：根据中华人民共和国药典（2010版，二部）附录ⅥC第一法测定熔点，测得的熔点为286-288℃。
本发明的另外一个目的，公开了维拉佐酮二盐酸盐新晶型的制备方法，通过将维拉佐酮溶于5—10倍二甲基甲酰胺中，通入干燥的氯化氢，或加入盐酸乙醚至PH2-3得到。上述非质子溶剂有二甲基甲酰胺，二甲基亚砜，四氢呋喃。
而分别在非质子性溶剂二甲基亚砜，四氢呋喃，乙腈中，加入盐酸乙醇，则分别得到其它3种晶型，记为1型，2型，3型。
上述四种晶型，不同于专利WO2002102794公开的维拉佐酮二盐酸盐那种晶型，令人惊奇的是，其中一种晶型，也就是本发明公开的维拉佐酮二盐酸盐新晶型具有优良的特性，该晶型溶解度大，这对药物发挥疗效极其重要，还具有纯度高，稳定性好，在工业生产上具有优越性，适合制剂工艺过程和长期储存。
所用的维拉佐酮，可参考文献US5532241和Journal of Medicinal Chemistry,2004,47(19):4684-4692, 提供的方法合成。化学结构经元素分析确证，后可经核磁共振氢谱（1H-NMR）、核磁共振碳谱（13C-NMR，）、质谱(Ms)等确证。
为了对比研究，可参考文献US5532241和Journal of Medicinal Chemistry,2004,47(19):4684-4692, 提供的方法合成维拉佐酮盐酸盐，再参考文献WO2002102794制得维拉佐酮盐酸盐的Ⅳ型，维拉佐酮二盐酸盐的ⅩⅢ型。
本发明的又一个目的，提供了包含维拉佐酮二盐酸盐新晶型的药物组合物。本发明的药物组合物制备如下：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体或液体载体结合，以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质，其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。
药物组合物以及单元剂型中含有的活性成份（本发明化合物）的量可以根据患者的病情、医生诊断的情况特定的加以应用，所用的化合物的量或浓度在一个较宽的范围内调节，活性化合物的量范围为组合物的1％～40％（重量）。
本发明还提供了维拉佐酮二盐酸盐新晶型在制造治疗忧郁症药物中的应用。
经大鼠在体试验，口服给予本发明的新晶型维拉佐酮二盐酸盐抑制5-HT再摄取的ID50为3.1mg／kg；给小鼠灌胃本品25～45 mg／kg能减少行为绝望和悬尾评分中的不运动时间，可用于制造治疗忧郁症的药物。
稳定性试验
结果：维拉佐酮二盐酸盐在强光、高温、高湿条件下从0—10天，外观、X粉末衍射、红外吸收光谱、热分析图谱均未发生变化，说明晶型稳定，无转晶发生，仍保持原来的晶型；另外有关物质、含量没有改变，说明新晶型化学稳定性良好，适合药物制剂的制造及长期储存。
溶解度实验
按照刘克非等人，沈阳药科大学学报，2010，27（11）：853,采用经典的平衡法测定 Ⅳ型 ，ⅩⅢ型，1型，2型，3型 ，
| Ⅳ型 | ⅩⅢ型 | 1型 | 2型 | 3型 | 本发明晶型 |
| 0.29 | 0.17 | 0.25 | 0.19 | 0.12 | 0.41 |
本发明晶型溶解度数据，以ug/ml表示。
说明书附图：
图1 维拉佐酮二盐酸盐新晶型的X射线衍射图；
具体实施方式：
下面结合实施例对本发明做进一步的说明，使本领域专业技术人员更好的理解本发明。实施例仅为解释性的，决不意味着它以任何方式限制本发明的范围。
本发明中所用的维拉佐酮（vilazodone，即1-[4-(5-腈基吲哚-3-基)丁基] -4-(2-胺甲酰-苯并呋喃-5-基)哌嗪，根据文献US5532241和Journal of Medicinal Chemistry,2004,47(19):4684-4692, 提供的方法合成，纯度98.4%(HPLC归一化法)。化学结构经元素分析确证，证明化学结构是正确的。分子式为C26H27N5O2，元素分析结果：
实测值（计算值），C:70.66(70.73),H:6.11(6.16),N:15.80(15.86)。
实施例1
在装有搅拌、温度计、冷凝器的1000ml反应瓶中，加入30克维拉佐酮和180ml二甲基甲酰胺，开动搅拌，加热升温到48℃—50℃，过滤，滤液冷至10℃-12℃，加入盐酸乙醚至PH2-3，然后冷至0℃-4℃，保温搅拌11小时。对析出的结晶进行过滤，用30ml无水乙醚均分三次洗涤，室内放置1小时，然后移至真空干燥箱中，室温真空干燥3小时，得26.1克维拉佐酮二盐酸盐白色结晶性粉末，熔点为286-288℃，纯度99.84%(HPLC归一化法)。
元素分析结果：
实测值（计算值），C:60.63(60.70),H:5.62(5.68),N:13.68(13.61),
Cl:13.75(13.78)；
该结晶性粉末的X射线衍射图见图1。仪器型号和测定条件：日本理学D/max 2500型衍射仪； CuKa 40Kv 100mA; 2θ扫描范围：0－50°；
实施例2
含有维拉佐酮二盐酸盐新晶型的颗粒剂
处方：新晶型的维拉佐酮二盐酸盐10克，乳糖650克，微晶纤维素30克，交联聚维酮68克，80克PEG-4000，羟丙基甲基纤维素110克，蒸馏水适量，制成1000袋。
工艺：PEG-4000与新晶型的维拉佐酮二盐酸盐共同粉碎，过80目筛，与其它物料混匀后用蒸馏水制软材、制粒、低温干燥后分装为颗粒剂。
实施例3
含有维拉佐酮二盐酸盐新晶型的胶囊
处方：新晶型的维拉佐酮二盐酸盐40克，丙二醇16ml，淀粉120克，硬脂酸镁26克，胶态二氧化硅35克，制成1000粒。
工艺：将新晶型的维拉佐酮二盐酸盐、淀粉、硬脂酸镁、胶态二氧化硅，用15%丙二醇水溶液润湿，混匀后过筛制粒，60℃干燥，整粒，填充胶囊。
实施例4
含有维拉佐酮二盐酸盐新晶型的片剂
处方：新晶型的维拉佐酮二盐酸盐20克，微晶纤维素30克，乳糖160克，16克PEG-4000，硬脂酸镁12克，25克聚维酮K30，交联羧甲基纤维素钠40克，滑石粉10克，蒸馏水适量，制成1000片。
工艺：PEG-4000与新晶型的维拉佐酮二盐酸盐共同粉碎，过80目筛，与其它物料混匀后用蒸馏水制软材，16目筛制颗粒，置干燥箱中于40-45℃干燥，16目筛整粒，硬脂酸镁加入干颗粒中混匀，压片。
Claims (7)
1.一种维拉佐酮二盐酸盐的晶型，其特征在于：用CuKa射线作为特征X射线粉末测定中，其图谱具有下列2θ衍射角和D值，
2θ衍射角的误差为0.2。
2.权利要求1所述的晶型，其特征在于：所述晶型的熔点为286-288℃。
3.权利要求1所述的维拉佐酮二盐酸盐晶型的制备方法，通过将维拉佐酮溶于非质子溶剂中，加入盐酸乙醚至pH2-3得到。
4.权利要求3所述的制备方法，其特征在于包括下列步骤：通过将维拉佐酮溶于5—10倍二甲基甲酰胺中，开动搅拌，加热升温到46℃—50℃，过滤，滤液冷至10℃-15℃，加入盐酸乙醚至PH2-3，然后冷至0℃-5℃，保温搅拌10—12小时。对析出的结晶进行过滤，用30ml无水乙醚均分三次洗涤，室内放置1小时，然后移至真空干燥箱中，室温真空干燥3小时，得到维拉佐酮二盐酸盐白色结晶性粉末。
5.一种含有权利要求1所述晶型的维拉佐酮二盐酸盐与一种或多种药学上可接受的载体组成的维拉佐酮二盐酸盐组合物。
6.权利所要求5所述的组合物，其特征在于该组合物用于制备口服制剂。
7.权利要求1所述晶型的维拉佐酮二盐酸盐在制造治疗忧郁症的药物中的应用。
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Address after: 300457 experimental building, 6 international biological medicine Joint Research Institute, No. 220 Dongting Road, Tianjin Development Zone, S614 Patentee after: Tianjin Han Yi Pharmaceutical Technology Co., Ltd. Address before: 300457 experimental building, 6 international biological medicine Joint Research Institute, No. 220 Dongting Road, Tianjin Development Zone, S614 Patentee before: Tianjin Han Tong consistent Drug Evaluation Technology Co., Ltd. |
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