CN1630631A - 新的文拉法星盐酸盐多晶型物及其制备方法 - Google Patents
新的文拉法星盐酸盐多晶型物及其制备方法 Download PDFInfo
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Abstract
本发明涉及热稳定度很高的新的文拉法星盐酸盐的无水结晶多晶型物,其制备方法,和其用途。
Description
技术领域
本发明涉及热稳定度很高的新的文拉法星盐酸盐的无水结晶多晶型物,其制备方法,和其用途。
背景技术
文拉法星(1-[2-(二甲氨基)-1-(4-甲氧苯基)乙基]环己醇)及其治疗上可接受的盐(本申请统称为文拉法星)是一元胺神经递质摄取抑制剂,其机制与临床抗抑郁剂活性有关。该机制也与生殖功能有关,它间接地影响下丘脑-垂体-卵巢轴。人们相信,文拉法星的作用机理与有效抑制一元胺神经递质血清素和去甲肾上腺素的摄取有关。在较低程度上,文拉法星也抑制多巴胺的再摄取。但是,它没有单胺氧化酶上的活性。
与经典的三环抗抑郁剂药物相反,文拉法星实际上对体外的毒蕈碱(muscaranic),组胺(histaminergic)或肾上腺素能受体没有亲合力。这些受体上的药理学活性与各种抗胆碱能药,镇静药,和心血管药物有关,它们的作用与三环抗抑郁剂一致。
美国专利No.5,506,270提出抑郁和使抑郁的人类女性的丘脑下部性闭经也可能使用文拉法星治疗。
美国专利No.5,530,013提出诱导认知促进作用,可以治疗哺乳动物的认知损伤。
美国专利No.5,744,474公开文拉法星可以人类尿失禁。
最近,美国专利No.5,916,923论述已经发现文拉法星可以治疗,预防,和控制哺乳动物(例如,人类)的肥胖,一般化的焦虑疾病,外伤后的应力疾病,经前期综合征(premenstrual syndrome),注意力不集中疾病(with and without hyperactivity),Gilles de la Tourette综合症,bulimia nervosa,和Shy Drager综合症。
美国专利No.6,274,171和国际专利公开No.WO 94/27589公开了文拉法星的缓释制剂。美国专利No.6,274,171论述文拉法星盐酸盐存在两个多晶型物,形式I和II。形式I和II特征X射线粉末衍射分别显示于图2和3。
发明概要
本发明提供新的文拉法星盐酸盐的无水结晶多晶型物。该结晶多晶型物比已知的由文拉法星盐酸盐形成的结晶热稳定程度更高。虽然形式I和II文拉法星盐酸盐的熔点分别为209和211℃(ΔH=125.8和130.3J/g),但本发明结晶多晶型物的熔点大约为219℃(ΔH=116J/g)。由于其稳定性,文拉法星盐酸盐的各种多晶型物的混合物可以形成该新的多晶型物的单一形式。此外,制备文拉法星盐酸盐的新的多晶型物或前体的剩余溶剂容易被除去。
本发明结晶多晶型物在大约下列的位置显示特性XRPD峰(用角度2θ表示):5.67,7.28,9.14,9.67,10.77,11.31,14.01,14.54,14.85,15.48,15.81,16.17,16.94,17.68,18.02,18.48,19.29,19.69,20.46,20.74,21.86,22.33,22.67,22.95,23.17,24.06,24.61,25.13,26.62,26.97,27.64,28.25,29.01,29.96,31.01,31.61,32.75,34.54,35.50,35.95和36.91。
本发明结晶多晶型物可以对哺乳动物给药,治疗抑郁症(包括但不限于,主要的压抑疾病,双极神经元疾病,和精神抑郁症),纤维肌瘤(fibromyalgia),焦虑,恐慌,空旷恐惧(agorophobia),外伤后紧张,经前的烦躁不安的(premenstrual snydrome),注意力欠缺(with andwithout hyperactivity),强迫性的强制疾病(包括拔毛发癖),社交焦虑,一般的焦虑,孤独症,精神分裂症,肥胖,神经性厌食症,神经性食欲过盛(bulimia nervosa),Gilles de la Tourette综合症,血管舒缩潮红(vasomotor flushing),古柯碱和酒癖,性功能紊乱(包括早泄),模棱两可的人格障碍,慢性疲劳综合症,尿失禁,疼痛(包括但不限于,偏头痛,慢性背痛,假肢痛,中枢性疼痛,神经性的疼痛如糖尿病性神经病变,和带状疱疹后的神经病),Shy Drager综合症,雷诺氏综合征。该结晶多晶型物还可以用于预防抑郁症的复发或再发生,诱导认知,治疗认知损伤,以及用于中断吸烟或其他烟草用途的食物疗法。另外,该结晶多晶型物可以用于治疗人类女性抑郁非使抑郁中的丘脑下部性闭经。这些方法包括对需要治疗的哺乳动物(例如,人类)有效量的本发明结晶多晶型物或本发明结晶多晶型物的文拉法星多晶型物的混合物。优选地,将文拉法星口服给药。
本发明另一个具体方案是包含本发明结晶多晶型物和,非强制性地,药学上可接受的载体或稀释剂的组合物。一般地,该药物组合物包含适量的有效治疗动物,如哺乳动物(例如人类)中的抑郁症或任何上述的适应症。按照本发明的一个优选方案,基于100%总重量文拉法星盐酸盐,该药物组合物包含至少约20,30,40,50,60,70,80,90,95,96,97,98,99,99.1,99.2,99.3,99.4,99.5,99.6,99.7,99.8,或99.9%重量比的本发明结晶多晶型物。按照本发明的另一个优选方案,基于100%总重量文拉法星盐酸盐,该药物组合物包含至少约20,30,40,50,60,70,80,90,95,96,97,98,99,99.1,99.2,99.3,99.4,99.5,99.6,99.7,99.8,或99.9%重量比的本发明结晶多晶型物。
该药物组合物可被掺入一种剂型,片剂或胶囊。
本发明结晶多晶型物可以通过将形式I或II的文拉法星盐酸盐或其混合物加热到至少约197℃,更优选至少约200℃的温度制备。按照一个具体方案,文拉法星盐酸盐被加热到约200℃。通常,文拉法星盐酸盐至少约加热60分钟,更优选至少约150分钟。形成的结晶可以通过本领域已知的任何方法回收。
另一个具体方案是制备基本上纯的文拉法星盐酸盐结晶多晶型物的方法。该方法包括得到基本上纯的形式的本发明文拉法星盐酸盐结晶多晶型物,然后转变成为基本上纯的文拉法星盐酸盐的另一个多晶型物,如形式I。基本上纯的文拉法星盐酸盐产物可以被掺入本领域已知的药物组合物和剂型。
附图的简要描述
图1是本发明无水文拉法星盐酸盐结晶多晶型物的特征X射线粉末衍射(XRPD)图谱。
图2是文拉法星盐酸盐形式I的特征XRPD图谱。
图3是文拉法星盐酸盐形式II的特征XRPD图谱。
图4是在氮气吹洗下,在密封的容器中,本发明无水文拉法星盐酸盐结晶多晶型物从25到240℃的差示扫描量热法(DSC)扫描图谱,扫描频率为10℃/分钟。
图5是在氮气吹洗下本发明无水结晶多晶型物从28到238℃的热重分析(TGA)图谱,扫描频率10℃/分钟。
发明的详细说明
术语“约”通常表示10%,优选5%,更优选1%内的给定值或范围。关于XRPD图谱的角度2θ的给定值或范围,术语“约”通常表示在0.2°2θ,优选0.1°,0.05°,或0.01°2θ内的给定值或范围。选择性地,术语“约”表示在本领域普通技术人员一般认为的容许标准误差的范围内。
本申请使用的术语“治疗”指预防,缓解,控制,或治疗需要治疗的症状或疾病。
本申请使用的术语“文拉法星盐酸盐”指混合物,例如,R和S文拉法星及其旋光纯的对映体的外消旋混合物。本发明结晶多晶型物可以是R型,S型,或混合物,例如,R和S文拉法星盐酸盐的外消旋混合物。
该结晶多晶型物具有基本上和图1显示的一致的XRPD图谱。图1XRPD图谱的峰位置和强度提供于以下表1。
表1
文拉法星盐酸盐多晶型物特征XRPD峰(用角度2θ表示)D-间距[以
埃(A)表示]和衍射线强度[以CPS表示]
角度2θ | d() | I(Counts per Second(CPS) |
5.67 | 15.57 | 309.09 |
7.28 | 12.14 | 828.73 |
9.14 | 9.67 | 766.93 |
9.67 | 9.14 | 262.26 |
10.77 | 8.21 | 303.39 |
11.31 | 7.82 | 728.55 |
14.01 | 6.31 | 224.07 |
14.54 | 6.09 | 807.87 |
14.85 | 5.96 | 887.19 |
角度2θ | d() | I(Counts per Second(CPS) |
15.48 | 5.72 | 830.41 |
15.81 | 5.60 | 617.50 |
16.17 | 5.48 | 357.33 |
16.94 | 5.23. | 728.55 |
17.68 | 5.01 | 338.29 |
18.02 | 4.92 | 312.91 |
18.48 | 4.80 | 753.93 |
19.29 | 4.60 | 1069.82 |
19.69 | 4.50 | 963.51 |
20.46 | 4.34 | 866.61 |
20.74 | 4.28 | 1084.34 |
21.86 | 4.06 | 365.61 |
22.33 | 3.98 | 187.75 |
22.67 | 3.92 | 259.14 |
22.95 | 3.87 | 240.39 |
23.17 | 3.84 | 343.83 |
24.06 | 3.70 | 264.69 |
24.61 | 3.62 | 403.19 |
25.13 | 3.54 | 498.24 |
26.62 | 3.35 | 479.23 |
26.97 | 3.30 | 783.01 |
27.64 | 3.23 | 338.01 |
28.25 | 3.16 | 294.56 |
29.01 | 3.08 | 452.07 |
29.96 | 2.98 | 237.53 |
31.01 | 2.88 | 348.88 |
31.61 | 2.83 | 478.42 |
32.75 | 2.73 | 332.38 |
34.54 | 2.60 | 347.78 |
角度2θ | d() | I(Counts per Second(CPS) |
35.50 | 2.53 | 338.55 |
35.95 | 2.50 | 315.92 |
36.91 | 2.43 | 221.30 |
特别地,该结晶多晶型物的特征峰(用角度2θ表示)在大约5.67,7.28,9.14,9.67,10.77,14.01,14.54,16.17,19.69和20.74。根据差示扫描量热法,该结晶多晶型物也在219℃熔化吸热。
本发明结晶多晶型物具有治疗,预防,或控制抑郁症和上述适应症的用途。对于动物的适当剂量可以通过本领域已知的方法测定。通常,对于需要的目的给与治疗的有效量。本申请公开的文拉法星盐酸盐结晶多晶型物的剂量通常为每天约75到约300毫克。
该结晶多晶型物可以被配制成药物组合物。优选地,该药物组合物包含适量的有效治疗动物,如人类中的需要的适应症的文拉法星结晶多晶型物。按照本发明的一个优选方案,基于100%总重量文拉法星盐酸盐,该药物组合物包含至少约20,30,40,50,60,70,80,90,95,96,97,98,99,99.1,99.2,99.3,99.4,99.5,99.6,99.7,99.8,或99.9%重量比的本发明结晶多晶型物。按照本发明的另一个优选方案,基于100%总重量文拉法星盐酸盐,该药物组合物包含至少约20,30,40,50,60,70,80,90,95,96,97,98,99,99.1,99.2,99.3,99.4,99.5,99.6,99.7,99.8,或99.9%重量比的本发明结晶多晶型物。
该药物组合物还可以基本上释放或完全文拉法星盐酸盐的其他结晶多晶型物,如形式I和II。术语“基本上游离的”和“基本上纯的”包括基于药物组合物总重量(或者基于药物组合物中的文拉法星盐酸盐的总重量)包含小于0.01,0.1,0.2,0.3,0.4,0.5,1或2%重量比的其他结晶多晶型物,如形式I或II或二者的药物组合物。
按照一个具体方案,该药物组合物包含从约25到约350毫克的文拉法星盐酸盐结晶多晶型物。更优选地,本发明药物组合物包含75毫克,150毫克或225毫克文拉法星盐酸盐结晶多晶型物。
该药物组合物也可能包括一种或多种药学上可接受的载体或稀释剂和赋形剂。术语“赋形剂”包括,但是不限于,适用于在药物制剂中使用的物质,并且加入该制剂以便促进该配制的稳定性和耐久性,如粘合剂,填充剂,澄清剂,缓冲剂,润湿剂,润滑剂,增甜剂,和增香剂。合适的赋形剂包括,但是不限于,纤维素,乙基纤维素,凝胶,羟丙基甲基纤维素,氧化铁,二氧化钛,乳糖,硬脂酸镁,和淀粉羟基乙酸钠。合适的药学上可接受的载体,稀释剂和赋形剂也包括公开于Remington′s,TheScience and Practice of Pharmacy,(Gennaro,A.R.,ed.,19thedition,1995,Mack Pub.Co.)的那些,该文献作为参考编入本申请。短语“药学上可接受的”指添加剂或组合物在对动物,如哺乳动物(例如人类)给药时,为生理学可容忍的,一般不产生过敏或相似的不良反应,如胃紊乱,眩晕等。
按照一个优选方案,药物组合物为缓释制剂,如美国专利No.6,274,171公开的制剂,该文献作为参考编入本申请。例如,缓释制剂可以包括由本发明结晶多晶型物,微晶纤维素,以及,非强制性地,羟丙基-甲基纤维素组成的球状体。该球状体优选地涂有由乙基纤维素和羟丙基甲基纤维素组成的涂膜组合物。
该药物组合物可以是剂型,如液体(例如,酏剂和悬浮液),胶囊,丸剂,或片剂。该药物组合物和文拉法星盐酸盐结晶多晶型物可以下列方式对动物,包括但不限于,哺乳动物(人类)给药:口服,静脉内,肌内注射,胃肠外,腹膜下,真皮下,颊服,皮下,透真皮,局部,直肠,阴道,或鼻腔内给药。组合物优选口服给药。
本发明结晶多晶型物可以通过将形式I或II的文拉法星盐酸盐或其混合物加热到至少约197℃,更优选至少约200℃的温度制备。按照一个具体方案,文拉法星盐酸盐被加热到约200℃。通常,文拉法星盐酸盐加热足够时间后形成本发明结晶多晶型物。优选地,文拉法星盐酸盐前体加热至少约60分钟,更优选至少约150分钟。通过加热文拉法星盐酸盐前体足够量的时间可以制备基本上纯的形式的该结晶多晶型物。
文拉法星盐酸盐可以通过本领域已知的任何方法制备,包括但不限于,美国专利Nos.4,535,186和4,761,501以及国际专利公开Nos.WO 00/32555,WO 00/32556,和WO 01/07397公开的方法,所有的文献作为参考编入本申请。
形成的结晶可以通过本领域已知的任何方法回收,如过滤,离心,或Buchner style过滤器,Rosenmund过滤器,或压力板和框。一般地,该结晶作为固体回收。
通过在乙醇中的乙酸乙酯中(例如,80%乙醇中的乙酸乙酯),该结晶多晶型物可以变为形成I。
正如以上的讨论,通过将一种或多种形式的文拉法星盐酸盐在约200℃加热足够的时间,可以制备基本上纯的形式的该结晶多晶型物。通过如上所述的方法,该基本上纯的结晶多晶型物可用于制备其他基本上纯的文拉法星盐酸盐的结晶多晶型物,如形式I。基本上纯的文拉法星盐酸盐产物可以被掺入本领域已知的药物组合物和剂型。
实施例
下列实施例是例证性的而不意味着对要求保护的发明的范围的限制。用作以下实施例中的原料的文拉法星盐酸盐可以通过本领域已知的任何方法制备。
实施例1
无水文拉法星盐酸盐的制备
将约100毫克形式II的文拉法星盐酸盐放进玻璃管形瓶,用氮气吹扫,然后加热封口。将封口的管形瓶放进油浴,在大约200℃(197℃到200℃)加热1小时或直到结晶的形态转变为乳白色结晶。
实施例2
无水文拉法星盐酸盐的制备
除在油浴中加热2.5小时而不是1小时之外,用500毫克形式II的文拉法星盐酸盐重复实施例1的步骤。
实施例3
无水文拉法星盐酸盐的制备
除使用铝管形瓶而不是玻璃管形瓶之外,重复实施例1的步骤。
实施例4
X射线粉末衍射(XRPD)
在干燥条件下,使用Thermo ARL of Ecublens.Switzerland的Scintag X2 X-Ray Diffraction System Mode l00-A02对本发明文拉法星盐酸盐结晶多晶型物进行XRPD。XRPD仪器具有下列参数:
扫描类型: 正常
开始角度: 3度
停止角度: 40度
点数: 1851点
分级大小: 0.02度
数据解析: 1600
扫描速率: 0.04
扫描方式: 分级
波长: 1.540562
衍射光学:
检测器:
类型:固定狭缝
X2结构:无
试管:
类型:固定狭缝
X2结构:无
结果显示于图1。
对形式I和II的文拉法星盐酸盐重复该步骤。形式I和II的结果分别显示于图2和3。
实施例5
固有的溶解速率
形式II和本发明结晶多晶型物的固有的溶解速率测定如下。通过使用Carver压模在1000psi的模具(Wood′s装置)中压缩100毫克各物质,制备文拉法星盐酸盐的小球。然后将制造的小球放进产生单接触面面积为0.5cm2的溶解装置(Vankel 7010 equipped with a Gary300 Ultraviolet/Visible Spectrophotometer)。通过USP 23(1995),section 711,page 1791(Dissolution,apparatus)的方法,使用100rpm的转速,在37℃测定900毫升水中的溶解速率。溶解介质在1.0厘米路程微型流量式试池中以10毫升/分钟的流速循环。在220纳米记录紫外线吸收。
形式II和本发明结晶多晶型物都显示24.7毫克/cm2-分钟的溶解速率。
实施例6
差示扫描量热法(DSC)
在氮气吹洗下,在25℃到240℃使用可以从Perkin-Elmer ofShelton,Connecticut得到的Pyris I DSC,以10℃/分钟的扫描频率在封口容器中进行本发明无水文拉法星盐酸盐结晶多晶型物的DSC量测。DSC扫描显示于图4。
图4显示在221℃吸热(熔化热为116焦耳/克),此时无水文拉法星盐酸盐熔化。文拉法星盐酸盐开始熔解的温度是219℃。
实施例7
热重分析(TGA)
在氮气吹洗下,将本发明文拉法星盐酸盐结晶多晶型物的样品从28加热到238℃,以10℃/分钟的扫描速率在可以从Perkin-Elmer ofShelton,Connecticut得到的Pyris I TGA中扫描。
本发明的范围不应受本申请公开的具体方案的限制。实际上,除本申请公开的改进之外,显然本领域技术人员很容易从上述说明书和附图作出改进。这样的改进应该属于附加的权利要求的范围。当然它的义意是近似的,并且由说明书所支持。
本申请自始至终在引用专利,专利申请,公开,步骤,等。它们全部的公开内容作为参考编入本申请。说明书和参考文献之间可以存在矛盾,可以对照本申请公开的术语。
Claims (23)
1.具有与图1显示的基本相同的X射线粉末衍射图谱的文拉法星盐酸盐。
2.权利要求1的文拉法星盐酸盐,其中文拉法星盐酸盐是无水的。
3.权利要求1的文拉法星盐酸盐,其中文拉法星盐酸盐的熔点大约为219℃。
4.具有与图1显示的基本相同的X射线粉末衍射图谱的基本上纯的文拉法星盐酸盐。
5.一种文拉法星盐酸盐结晶多晶型物,其X射线粉末衍射图谱中以角度2θ表示的特征峰在大约5.67,7.28,9.14,9.67,10.77,11.31,14.01,14.54,14.85,15.48,15.81,16.17,16.94,17.68,18.02,18.48,19.29,19.69,20.46,20.74,21.86,22.33,22.67,22.95,23.17,24.06,24.61,25.13,26.62,26.97,27.64,28.25,29.01,29.96,31.01,31.61,32.75,34.54,35.50,35.95和36.91。
6.一种文拉法星盐酸盐结晶多晶型物,其X射线粉末衍射图谱中以角度2θ表示的特征峰在大约5.67,7.28,9.14,9.67,10.77,14.01,14.54,16.17,19.69,和20.74。
7.一种包含治疗有效量的权利要求1到6中任何一项的文拉法星盐酸盐和药学上可接受的载体或稀释剂的药物组合物。
8.按照权利要求7的药物组合物,其中文拉法星盐酸盐基本上是纯的。
9.按照权利要求7的药物组合物,其中基于该药物组合物中100%总重量的文拉法星盐酸盐,该药物组合物包含少于1%重量比的X射线粉末衍射图谱与图1显示的基本上相同的文拉法星盐酸盐结晶多晶型物。
10.按照权利要求7到9任何一项的药物组合物,其中该组合物包含大量球状体,该球状体包含文拉法星盐酸盐。
11.治疗哺乳动物抑郁症的方法,其中包括对该哺乳动物使用抗抑郁症有效量的权利要求1到6任何一项的文拉法星盐酸盐。
12.治疗哺乳动物一般化的焦虑疾病的方法,其中包括对该哺乳动物使用有效量的权利要求1到6任何一项的文拉法星盐酸盐。
13.治疗哺乳动物社交的的焦虑疾病的方法,其中包括对该哺乳动物使用有效量的权利要求1到6任何一项的文拉法星盐酸盐。
14.治疗哺乳动物外伤后紧张的疾病的方法,其中包括对该哺乳动物使用有效量的权利要求1到6任何一项的文拉法星盐酸盐。
15.治疗哺乳动物恐慌疾病的方法,其中包括对该哺乳动物使用有效量的权利要求1到6任何一项的文拉法星盐酸盐。
16.预防哺乳动物恐抑郁症复发或再发生的方法,其中包括对该哺乳动物使用有效量的权利要求1到6任何一项的文拉法星盐酸盐。
17.一种制备X射线粉末衍射图谱与图1显示的基本上相同的无水文拉法星盐酸盐的方法,该方法包括将形式I或II的文拉法星盐酸盐或其混合物在至少约197℃加热足够的时间以形成无水的文拉法星盐酸盐。
18.按照权利要求16的方法,其中文拉法星盐酸盐加热到至少约200℃。
19.按照权利要求16的方法,其中文拉法星盐酸盐至少加热约60分钟。
20.按照权利要求18的方法,其中文拉法星盐酸盐至少加热150分钟。
21.一种制备基本上纯的文拉法星盐酸盐结晶多晶型物的方法,该方法包括:
(a)得到基本上纯的X射线粉末衍射图谱与图1显示的基本上相同的文拉法星盐酸盐;以及
(b)将步骤(a)的文拉法星盐酸盐转变成为不同的结晶多晶型物。
22.按照权利要求21的方法,其中步骤(b)形成的文拉法星盐酸盐是形式I的文拉法星盐酸盐。
23.按照权利要求21的方法,其中步骤(b)形成的文拉法星盐酸盐是形式II的文拉法星盐酸盐。
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US20020183553A1 (en) * | 2000-10-19 | 2002-12-05 | Ben-Zion Dolitzky | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US6906087B2 (en) * | 2000-10-31 | 2005-06-14 | Ciba Specialty Chemicals Corpation | Crystalline forms of venlafaxine hydrochloride |
KR20070045278A (ko) * | 2004-07-22 | 2007-05-02 | 와이어쓰 | 신경계 질환 및 장애의 치료 방법 |
MX2007000853A (es) * | 2004-07-22 | 2007-03-26 | Wyeth Corp | Procedimiento para el tratamiento de trastornos y dolencias del sistema nervioso. |
US20060020014A1 (en) * | 2004-07-22 | 2006-01-26 | Wyeth | Method for treating nervous system disorders and conditions |
JP2009502798A (ja) * | 2005-07-21 | 2009-01-29 | ワイス | 神経系障害および状態の処置方法 |
EP1824815A2 (en) * | 2005-10-19 | 2007-08-29 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of highly pure 1-[2-dimethylamino-(4-methoxyphenyl) ethyl]cyclohexanol hydrochloride |
NZ599480A (en) * | 2007-02-21 | 2013-10-25 | Sunovion Pharmaceuticals Inc | Solid forms comprising (-)-o-desmethylvenlafaxine and uses thereof |
CA2812227C (en) | 2010-10-01 | 2015-11-24 | Shan Dong Luye Pharmaceutical Co., Ltd. | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods for preparing the same and use of the same |
IN2015DN01662A (zh) | 2012-09-18 | 2015-07-03 | Auspex Pharmaceuticals Inc | |
PL3265085T3 (pl) | 2015-03-06 | 2022-11-07 | Auspex Pharmaceuticals, Inc. | Sposoby leczenia zaburzeń związanych z nieprawidłowymi ruchami mimowolnymi |
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US6440457B1 (en) | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
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TW344661B (en) * | 1993-11-24 | 1998-11-11 | Lilly Co Eli | Pharmaceutical composition for treatment of incontinence |
US5530013A (en) * | 1994-02-14 | 1996-06-25 | American Home Products Corporation | Venlafaxine in the inducement of cognition enhancement |
US5506270A (en) * | 1995-01-30 | 1996-04-09 | American Home Products Corporation | Venlafaxine in the treatment of hypothalamic amenorrhea in non-depressed women |
US6274171B1 (en) * | 1996-03-25 | 2001-08-14 | American Home Products Corporation | Extended release formulation of venlafaxine hydrochloride |
UA77145C2 (en) * | 1997-11-05 | 2006-11-15 | Wyeth Corp | Extended release dosage formulation |
US20020183553A1 (en) * | 2000-10-19 | 2002-12-05 | Ben-Zion Dolitzky | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
CZ20031298A3 (cs) * | 2000-10-19 | 2003-10-15 | Teva Pharmaceutical Industries Ltd. | Způsob přípravy krystalické báze venlafaxinu a nových polymorfů hydrochloridu venlafaxinu |
US6906087B2 (en) * | 2000-10-31 | 2005-06-14 | Ciba Specialty Chemicals Corpation | Crystalline forms of venlafaxine hydrochloride |
AU2001235970A1 (en) | 2000-12-07 | 2002-06-18 | Dr. Reddy's Research Foundation | Novel crystalline polymorphic forms of venlafaxine hydrochloride and a process for their preparation |
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IL162255A0 (en) | 2005-11-20 |
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JP2005511736A (ja) | 2005-04-28 |
US20030109585A1 (en) | 2003-06-12 |
ZA200405248B (en) | 2005-10-03 |
TW200301101A (en) | 2003-07-01 |
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CA2467593A1 (en) | 2003-06-19 |
AR037744A1 (es) | 2004-12-01 |
US7030164B2 (en) | 2006-04-18 |
EP1451145A1 (en) | 2004-09-01 |
US20060074131A1 (en) | 2006-04-06 |
WO2003050075A1 (en) | 2003-06-19 |
BR0214742A (pt) | 2004-09-14 |
AU2002348266A1 (en) | 2003-06-23 |
KR20050044673A (ko) | 2005-05-12 |
HUP0402524A2 (hu) | 2005-03-29 |
NZ533363A (en) | 2005-10-28 |
CO5580818A2 (es) | 2005-11-30 |
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