CN1509169A - 对映体纯艾司西酞普兰的用途 - Google Patents
对映体纯艾司西酞普兰的用途 Download PDFInfo
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Abstract
本发明涉及对映体纯艾司西酞普兰和/或其低剂量药物在改善治疗抑郁症中的应用，尤其是用于治疗严重的抑郁性障碍、神经症性障碍、急性应激性疾病、进食障碍疾患(例如食欲过盛、食欲缺乏和肥胖)、恐怖症、精神抑郁症、月经前综合征、认知障碍、冲动控制障碍、注意力不集中的过度反应症或药物滥用。所述药物也可用于治疗“对治疗有抗性的”的严重的抑郁性障碍患者。
Description
本发明涉及对映体纯艾司西酞普兰(escitalopram，INN名)或其可药用盐在制备药物、尤其是用于治疗严重的抑郁性障碍(majordepression disorder)药物中的应用，所述艾司西酞普兰是已知抗抑郁药物西酞普兰(citalopram)的S-对映体，即(S)-1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃甲腈。
发明背景
选择性5-羟色胺再摄取抑制剂(下称SSRIs)例如西酞普兰，由于其相对于传统三环抗忧郁药所表现出的有效、耐受性好和良好的安全特性，已成为治疗抑郁症，某些形式的焦虑和社交恐怖症的首选治疗剂。
然而，对抑郁症和焦虑症的临床研究表明，对SSRIs无反应或抗性，即在治疗的头6周期间没有实现至少40-60％的症状减轻是显著的，即高达30％。
然而，SSRIs的治疗作用存在着迟滞现象。在治疗的第-周内，症状有时甚至会加重。即使是那些对SSRIs有应答的个体，也需要几周的治疗才能减轻症状。
另外，性功能障碍是所有SSRIs通常会引起的副作用。
不解决这些问题，抑郁和焦虑症的药物疗法将不可能取得实质性进展。
艾司西酞普兰是已知抗抑郁药物西酞普兰的S-对映体，具有如下结构式：
式I
US4,943,590披露了艾司西酞普兰及其制备方法。西酞普兰具有立体选择性，即S-对映体的5-HT-再摄取抑制作用，因此相应地也公开了所述对映体潜在的抗抑郁作用。基本上所有5-HT-再摄取抑制作用以及由此产生的抗抑郁作用均与S-对映体有关。从艾司西酞普兰的立体选择性来看，可预期其治疗抑郁的效力是外消旋体的2倍。
WO103694A1涉及艾司西酞普兰在治疗包括焦虑状态和惊恐发作在内的神经症性障碍(neurotic disorders)中的应用。
目前，业已惊奇地发现R-西酞普兰的存在对艾司西酞普兰的效力有负影响，并且药理学和临床研究也发现艾司西酞普兰的效力大大高于外消旋体效力的2倍。
此外，在动物模型和临床研究中还发现艾司西酞普兰的起效要快于外消旋体和其他SSRIs，并且在各种动物模型中达到了更为完全的反应。临床研究表明，对于那些对传统SSRIs没有反应的抑郁患者而言，艾司西酞普兰可能是有效治疗药物。
R-对映体对S-对映体的效力的令人惊异的负影响的机制还不清楚。-种可能的解释是R-对映体可能对S-对映体转运通过血脑屏障有负影响。或者，R-西酞普兰可能传达5-HT释放的局部反馈抑制，或者R-对映体可能调节S-对映体的作用。
发明描述
本发明涉及低剂量的和/或包含不到3％w/w R-西酞普兰的艾司西酞普兰在制备药物组合物中的应用。
在另一方面，本发明涉及-种药物组合物，其特征在于包括含有低于3％w/w R-西酞普兰的艾司西酞普兰为活性成分。
在另一方面，本发明涉及艾司西酞普兰在治疗严重的抑郁性障碍中的应用，其特征在于艾司西酞普兰的每日使用剂量小于10mg。
如上所述，本发明基于R-西酞普兰对艾司西酞普兰的效力有负影响这样一个发现。这可以在5-HT-再摄取作用的功能性体内药理学模型和研究中和/或在行为模型(例如抑郁模型)中有所体现。
业已发现，与双倍量的西酞普兰-外消旋体相比，艾司西酞普兰表现出显著的改进和/或能得到更完全的反应。因此，在固定剂量的研究中已发现，经MADRS评定量表(rating scale)和临床总体印象(CGI，严重性以及改善程度)的测定，10mg剂量艾司西酞普兰具有至少与40mg剂量的西酞普兰相同的作用。
还发现，与西酞普兰-外消旋体相比，艾司西酞普兰在动物模型中的起效更快。在慢性轻度应激模型中也发现了这-现象(Willner P.，Psychopharmachology 1997，134，319-329)。在-项对严重的抑郁性障碍患者(在初期治疗)所进行的8-周的双盲、随机、安慰剂-对照、可变-剂量研究中，艾司西酞普兰和西酞普兰与安慰剂的比较结果证实了这种作用。患者接受10mg艾司西酞普兰(155个患者)、20mg西酞普兰(160个患者)和安慰剂(154个患者)。1周后，艾司西酞普兰表现出了作用，而西酞普兰没有表现出明显的作用。
所有这些作用是非常令人惊奇的，因为现有技术中认为R-对映体对S-对映体的作用并没有影响，由此认为艾司西酞普兰的效力应仅是外消旋体的2倍。
另一个优点是：较低剂量的艾司西酞普兰有效的事实表明，在进行有效治疗的同时其副作用较低，尤其是减少5-羟色胺再摄取抑制剂的用量可降低SSRI诱发的性功能障碍和睡眠障碍的风险。
发明详述
艾司西酞普兰优选以草酸盐形式使用，优选为结晶草酸盐。
此外，所用艾司西酞普兰中，R-西酞普兰的含量不超过优选2％w/w，最优选1％w/w。在本说明书上下文中，R-西酞普兰的百分比是以相对于艾司西酞普兰含量的“w/w％”表示的。
本发明药物组合物优选用于治疗抑郁症，尤其是用于治疗严重的抑郁性障碍、神经症性障碍、急性应激性疾病、进食障碍疾患(例如食欲过盛、食欲缺乏和肥胖)、恐怖症、精神抑郁症、月经前综合征、认知障碍、冲动控制障碍、注意力不集中的过度反应症或药物滥用。
在本说明书和权利要求书的上下文中，术语“神经症性障碍”是指-类精神障碍，包括焦虑状态，尤其是一般焦虑症(generalisedanxiety disorder)和社交焦虑症、外伤后应激性疾病、强迫性神经失调和惊恐发作。
术语“一般焦虑症”、“社交焦虑症”、“外伤后应激性疾病”和“强迫性神经失调”如在DSM IV中所定义。
术语“惊恐发作”涉及与惊恐发作相关任何疾病的治疗，这些疾病包括出现惊恐发作时的惊恐性障碍、特异性恐怖症、社交恐怖症和广场恐怖症。这些疾病进一步如在DSM IV中所定义。
术语“惊恐性障碍的治疗”是指减少发作次数或预防发作和/或减轻发作的严重程度。同样地，一般焦虑症、社交焦虑症、外伤后应激性疾病和强迫性神经失调的治疗包括治疗或预防这些疾病或者减轻疾病症状。
在药理学和临床研究的基础上，优选的适应征为严重的抑郁性障碍和强迫性神经失调。
其他优选的应用是治疗神经症性障碍。
所述组合物尤其可用于治疗对传统SSRI初治无效的患者，尤其是对传统SSRI初治无效的严重的抑郁性障碍患者。这类对治疗有抗性的患者可特别定义为：经西酞普兰或其他市售SSRIs治疗后有40-60％症状没有减轻的患者。进一步的定义参见：Kornstein SC和SchneiderRK，Clinical features of treatment-resistant depression，JClin Psychiatr 2001，62，增刊16，18-25；Sackeim HA，Thedefinition和meaning of treatment-resist ant depression，J.Clin Psychiatr 2001，62增刊16，10-17；和Nierenber AA和DeCecco LM，Definitions of antidepressant treatment response，remission，non-response，partial response，and other relevantoutcomes：A focus on treatment-resistant depression，J ClinPsychiatr 2001，62增刊16，5-9。
本发明药物组合物可包括含有2.5-20mg艾司西酞普兰的艾司西酞普兰单剂量制剂。
就本发明所用艾司西酞普兰的作用而言，低剂量即有效，即日剂量低于10mg艾司西酞普兰，例如7.5mg或更低，例如7.5或5mg每天。
本发明药物组合物优选为口服制剂，优选为片剂。
这样，将活性成分与常规辅剂和/或稀释剂混和，接着用常规压片机压制所得混合物，即可制得片剂。示例性辅剂或稀释剂包括：玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等。可采用能与所述活性成分配伍的任何其他通常用于这样的目的的辅剂或稀释剂，例如着色剂、矫味剂、防腐剂等。
也可将活性成分和可能的添加剂溶于部分注射用溶剂(优选灭菌水)中，将溶液调至所需体积，溶液灭菌后充入适宜的安瓿或小玻璃瓶中，从而制得注射用溶液剂。可加入本领域任何适宜的常规添加剂，例如调渗透压剂(tonicity agents)、防腐剂、抗氧化剂等。
临床研究
共471位患者随机参与研究。所有-患者-治疗组(all-patient-treated set)包括469位患者，全分析组(full-analysis set)包括468位患者。其中全分析组中的艾司西酞普兰组有155位患者，西酞普兰组有159位患者，安慰剂组有154位患者。
每一治疗组中的男女比例约为1∶3，几乎所有患者均为白种人(Caucasian)。平均年龄为43岁(SD为11)。作为基线，治疗组的平均MADRS总评分约为29，这表示中等至严重病患者。
对MADRS总评分的平均变化(经校正)所进行的效力分析表明，由第1周(p＝0.023)至第4周(p＝0.002)(观察病例)，艾司西酞普兰的治疗作用显著优于安慰剂。在第4周时(最后观察)，艾司西酞普兰与安慰剂间MADRS总评分的经校正的平均变化为2.7点，大于(p＝0.002)西酞普兰与安慰剂间统计意义上的非显著性差异(1.5点)。
在CGI改善和严重性分量表(subscale)方面，艾司西酞普兰从第1周起显著优于安慰剂(p＜0.05)(观察病例)，而西酞普兰在4周期间与安慰剂间没有统计意义上的差异。在第4周时(最后观察)，艾司西酞普兰在统计意义上显著优于安慰剂，而西酞普兰与安慰剂间没有统计意义上的显著性差异。
Claims (19)
1.含有低于3％w/w R-西酞普兰的艾司西酞普兰在制备药物组合物中的用途。
2.根据权利要求1的用途，其特征在于所用艾司西酞普兰为草酸盐、优选结晶草酸盐形式。
3.根据权利要求1或2的用途，其特征在于所用的艾司西酞普兰包含不超过2％w/w的R-西酞普兰。
4.根据权利要求3的用途，其特征在于艾司西酞普兰包含不超过1％w/w。
5.根据权利要求1-4之一的用途，其特征在于所述药物组合物用于治疗抑郁症，尤其是用于治疗严重的抑郁性障碍，神经症性障碍，急性应激性疾病，进食障碍疾患例如食欲过盛、食欲缺乏和肥胖，恐怖症，精神抑郁症，月经前综合征，认知障碍，冲动控制障碍，注意力不集中的过度反应症或药物滥用。
6.根据权利要求5的用途，其特征在于所述药物组合物用于治疗严重的抑郁性障碍。
7.根据权利要求5的用途，其特征在于所述药物用于治疗神经症性障碍。
8.根据权利要求5-7之一的用途，其特征在于所述药物组合物用于治疗对传统SSRI初治无效的患者。
9.根据权利要求8的用途，其特征在于所述药物组合物用于治疗对传统SSRI初治无效的严重的抑郁性障碍患者。
10.药物组合物，其特征在于包括含有低于3％w/w R-西酞普兰的艾司西酞普兰为活性成分。
11.根据权利要求10的药物组合物，其特征在于包括含有不超过2％w/w R-西酞普兰的艾司西酞普兰为活性成分。
12.根据权利要求11的药物组合物，其特征在于包含不超过1％w/w的艾司西酞普兰。
13.根据权利要求10-12之一的药物组合物，其特征在于它是包含2.5-20mg艾司西酞普兰的单位剂量制剂。
14.根据权利要求13的药物组合物，其特征在于它是包含不超过10mg艾司西酞普兰的单位剂量制剂。
15.根据权利要求14的药物组合物，其特征在于它是包含不超过7.5mg、优选5.0mg艾司西酞普兰的单位剂量制剂。
16.根据权利要求10-15之一的药物组合物，其特征在于它是口服制剂，优选为片剂。
17.艾司西酞普兰在治疗严重的抑郁性障碍中的应用，其特征在于艾司西酞普兰的日剂量低于10mg。
18.艾司西酞普兰在治疗严重的抑郁性障碍中的应用，其特征在于艾司西酞普兰的日剂量为或低于7.5mg。
19.艾司西酞普兰在治疗严重的抑郁性障碍中的应用，其特征在于艾司西酞普兰的日剂量为5.0mg。
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| CN100353939C (zh) * | 2006-01-05 | 2007-12-12 | 昆明积大制药有限公司 | 含西酞普兰和环糊精的抗抑郁口服药用组合物 |
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| US20040192766A1 (en) | 2004-09-30 |
| NO20034538D0 (no) | 2003-10-09 |
| KR20100012089A (ko) | 2010-02-05 |
| PL367480A1 (en) | 2005-02-21 |
| US20080004338A1 (en) | 2008-01-03 |
| HRP20030744A2 (en) | 2005-06-30 |
| SK14612003A3 (sk) | 2004-04-06 |
| MEP5908A (xx) | 2010-02-10 |
| MXPA03008777A (es) | 2004-02-12 |
| US20040198811A1 (en) | 2004-10-07 |
| NO20034538L (no) | 2003-10-09 |
| IS6954A (is) | 2003-09-15 |
| AR033308A1 (es) | 2003-12-10 |
| US20040192765A1 (en) | 2004-09-30 |
| BG108379A (bg) | 2004-11-30 |
| WO2002087566A1 (en) | 2002-11-07 |
| US20040192764A1 (en) | 2004-09-30 |
| IL158031A0 (en) | 2004-03-28 |
| UA82828C2 (en) | 2008-05-26 |
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