CN108289967A - 用于光动力学诊断的金丝桃素配制剂 - Google Patents
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Abstract
在早期识别癌症特别是膀胱癌中可作为光敏剂使用的配制剂，其包含结合到聚乙烯吡咯烷酮上或与聚乙烯吡咯烷酮复合的金丝桃素钠盐。
Description
本发明涉及新型金丝桃素配制剂。
膀胱癌是尿路的最常见癌症。男性遭受膀胱癌的情况是女性的三倍以上。它是男性第七种最多被诊断出来的癌症类型(Ferlay等人，2013)。约75-85％具有新诊断出膀胱癌的患者显示非肌层浸润性膀胱肿瘤，即局限于粘膜的肿瘤。在此涉及原位癌(Tis)、Ta或TI的肿瘤阶段(Babjuk等人，2015)。在非肌层浸润性膀胱癌的情况下，复发率是很常见的。在第一年内再次出现的可能性为15-61％，五年后再次出现的可能性为31-78％(Witjes,Douglass,2007)。一旦成为患者，高反复率需要多年的监控和后续观察。
非肌层浸润性膀胱癌的最常见症状是血尿症。此外还可能出现下尿路的刺激性症状或疼痛。体检是不能给出潜在非肌层浸润性膀胱肿瘤的结论的(Babjuk等人，2015)。用内窥镜和白光照明(白光膀胱镜)以及组织样品的摘取成为第一手诊断。这些方法对于外生性肿瘤是可靠的。扁平癌(特别是Tis)、发育不良、多焦点增长和显微镜病变对于识别是更为重要的，则在白光膀胱镜检查的情况下经常被忽视。
荧光膀胱镜检查的方法(也称为光动力学诊断(PDD))改善了非肌层浸润性膀胱癌，特别是Tis，的识别率，并由此减少复发率(Burger等人，2013；Kausch等人，2010；Stenzel等人，2010)。
所述光动力学诊断(PDD)利用特定化合物的光活性特点，所谓的光敏剂，其优选在肿瘤组织中富集并改善正常和肿瘤组织之间的光学分界。
所述光动力学诊断(PDD)的基本原理基于一种两步法，其包括光敏剂的全身或局部应用并通过用具有适宜波长的可见光照射激活光敏剂。
在非肌层浸润性膀胱癌的检查中的“黄金标准”是白光膀胱镜检查。但在怀疑Tis的情况下，推荐使用荧光膀胱镜检查(Babjuk等人，2015)，经此能平均发现20％更多的Tis(Witjes等人，2010)。
卟啉前体5-氨基乙酰丙酸(5-ALA)和衍生物六氨基乙酰丙酸(HAL)在荧光诊断中使用。这两种物质是前药。通过前药的代谢产生用于PDD的光活性分子。在膀胱癌指示中唯一作为药物批准用于PDD的物质是六氨基乙酰丙酸
金丝桃素(1,3,4,6,8,13-六羟基-10,11-二薄荷基菲并(1,10,9,8-opqra)二萘嵌苯-7,14-二酮)作为癌细胞的光敏剂和指示剂，特别是用于检定泌尿道上皮的非肌层浸润性癌的特性，是已知的。金丝桃素不是前药，并且必须不能在组织中代谢，一旦金丝桃素在组织中积蓄则可直接用具有适宜波长的光激动。然而，纯金丝桃素是疏水性的且不溶于水。出于这种原因，在过去的实践研究中使用水溶性聚合物聚乙二醇(PEG)或在临床研究中血清蛋白作为有效的金丝桃素转运体/载体，从而将不溶性金丝桃素带入靶细胞(D'Hallewin等人，2000und 2002；Olivo等人，2003；Pytel等人，2002)。
金丝桃素的溶解性可通过助剂聚乙烯吡咯烷酮(“Povidon”，PVP)的存在而被提高(WO 01/89576A2)。
将出自25mg的PVP和0.25mg的金丝桃素的配制剂临床研究于57名患者(Kubin等人，2008)。就扁平的病灶(Tis和发育不良)而言，在病变平面上，用PVP-金丝桃素支持的PDD，对Tis达到100％的发现率，对发育不良达到85％的发现率，而在白光膀胱镜下仅33％(Tis)和31％(发育不良)被发现。
对病变平面改善的发现率也表现在患者平面上：16％的患者，PVP-金丝桃素支持的PDD发现在白光膀胱镜中被忽视的病变。PVP-金丝桃素溶液的滴注时间(在膀胱中的滞留时间)在60-220分钟(平均111±39(SD)分钟(Kubin等人，2008))。
即使已知的PDD研究实现了良好的结果，重要问题仍未解决。至少60分钟的长滴注时间(这意味着所施用的溶液在患者的膀胱中停留)成为患有非肌层浸润性膀胱癌的患者的负担，其很常见地承受疼痛或痉挛。
本发明的任务在于，提供无菌的制药学金丝桃素配制剂，其可大规模制备并具有相应的长时间的稳定性。这种金丝桃素配制剂应当作为膀胱癌诊断比已知配制剂更加毫无问题地使用。
上述任务由具有权利要求1的特征的金丝桃素配制剂解决。
根据本发明的配制剂的优选且有利的实施形式是从属权利要求的主题。
令人惊奇地显示，仅当金丝桃素以盐存在时，根据本发明的金丝桃素配制剂才稳定并在临床条件下可应用。
在临床研究的范围内显示，根据本发明的金丝桃素配制剂特别好地适用于发现疑有非肌层浸润性膀胱癌的患者中的恶性病变。经此，允许根据本发明的金丝桃素配制剂显著较短的滴注时间而不损害PDD的结果，其意味着有利地降低了患者的负担。
针对非肌层浸润性膀胱癌的PDD，令人惊奇地具有剂量为22.5mg PVP和0.225mg金丝桃素的根据本发明的配制剂与30至最多50分钟的滴注时间的组合应用表明为最佳剂量。
借助于根据本发明的配制剂可以在30至50分钟的滴注时间下在35％的患者中鉴定出被白光膀胱镜忽视的Tis-病变。
肿瘤的完全摘除(切除术)是患者治疗的第一重要的步骤。通常肿瘤组织的完全切除术是困难的。这导致，肿瘤物质不被发觉并遗留在患者的膀胱中。出于这种原因，特别重要的是，完全地发觉肿瘤组织的边缘和边界并去除。
具有金丝桃素含量为0.225mg(实施例1)的根据本发明的配制剂的应用显示出组织细节的可识别性的改善，特别是鉴于肿瘤的边缘区。经此使得恶性和良性组织之间的区别变得容易且肿瘤可被完全地去除。
恶性和良性组织之间的这种改善的区分，用含量为0.500mg的金丝桃素和仅为15分钟的滴注时间同样得以实现。
在Tis病变之后，关联着极其高的复发率和很高的进展可能性(这意味着肿瘤的发展进入更高级的阶段或出现转移)，借助于根据本发明的金丝桃素配制剂，改善的发现率和由此完全的肿瘤去除对于进一步的疾病过程是显著的优点。
在根据本发明的配制剂的使用下所需要的15、平均30至最多50分钟的滴注时间相比那些用六氨基乙酰丙酸的PDD所使用的滴注时间显著更短。在平均30分钟的滴注时间后就已经可借助于所述金丝桃素-配制剂诊断恶性病变。这种显著缩短的滴注时间使非肌层浸润性膀胱癌患者轻松了很多，并提高了在所需作用时间内保持的可能性。
以下描述根据本发明的金丝桃素配制剂的实施例：
用于制备具有活性物质金丝桃素钠盐的配制剂的一般性方法：
目的是制备在光动力诊断学领域中的用作为光敏剂的含有金丝桃素的配制剂。
根据本发明的配制剂由金丝桃素的盐，特别是由金丝桃素钠盐制备。
为了定义原材料的金丝桃素含量，除了含量测定主要记录水含量和在金丝桃素钠盐的情况下钠的份额。化学-物理特性可影响到制药学药剂的配制。
对于临床应用，根据本发明的配制剂的稳定性是必需的。所述稳定性通过终产品的组成得以保证并同时还涉及制备方法。通过所使用的缓冲系统还可以在终产品的制备期间直至冻干使散装溶液达到足够的稳定性。
作为缓冲系统可考虑不同的添加剂，既对散装溶液也对重构溶液优选达到生理相容的pH值和在用50ml注射用水重构后290mOsmol/kg的渗透压。磷酸盐或柠檬酸盐缓冲系统可首先被使用。
在由上述成分制得散装溶液之后，将相应量的散装溶液填充入注射瓶并冻干。
实施例1：
由金丝桃素钠盐制备具有目标称重为27.0mg的金丝桃素的溶液。
向562.5mg的PVP k25添加5.0g的金丝桃素溶液并完全溶解。
用磷酸盐缓冲溶液将该溶液量化加满到250.0g。该溶液的终浓度为0.0225mg金丝桃素/g溶液。
用于冻干将定义量的如此获得的散装溶液填充入注射瓶并用相应的冻干程序制备最终的冻干剂。
实施例2：
如实施例1的指示进行制备，其中替代PVP k25使用PVP k17用于金丝桃素钠盐的复合。
实施例3:
如实施例1的指示进行制备，其中替代PVP k25使用PVP k30用于金丝桃素钠盐的复合。
实施例4:
如实施例1、2或3的指示进行制备，其中替代磷酸盐缓冲液使用柠檬酸缓冲溶液。
如在实施例1至4中所描述制备的散装溶液，可以以不同的金丝桃素含量生产。
由金丝桃素母液(由金丝桃素钠盐制备)可在进一步加工前制备如下稀释液：
-向0.4g在实施例1中所述的金丝桃素溶液添加定义量溶剂并均化。在这种情况下在下一步骤中仅添加187.5mg的PVP(不同类型的PVP是可能的)用于形成复合物。由此在最终的散装溶液中实现0.0075mg金丝桃素/g溶液的终浓度。
-向0.2g在实施例1中所述的金丝桃素溶液添加定义量溶剂并均化。在这种情况下在下一步骤中仅添加62.5mg的PVP(不同类型的PVP是可能的)用于形成复合物。由此在最终的散装溶液中实现0.0025mg金丝桃素/g溶液的终浓度。
在临床研究中，将根据实施例1的金丝桃素配制剂以剂量为22.5mg的PVP和0.225mg的金丝桃素、平均时长30至35分钟，最多直至50分钟向患者膀胱内滴注。之后进行膀胱镜检查，首先是白光、之后是荧光。可疑的病变被提取并借助组织发生学研究进行分类。
在总共20名患者中Tis病变可被发现并被组织发生学证实。在此使用根据本发明的金丝桃素配制剂的PDD在35％的患者中表现出发现Tis的决定性优势。在这些患者中，若无使用根据本发明的金丝桃素配制剂的PDD，则不被发现。
参考：
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D′Hallewin MA，Kamuhabwa AR，Roskams T，de Witte PAM，Baert L.Hypericin-based fluorescence diagnosis of bladder carcinoma.BJU International 2002；89：760-763
D′Hallewin MA，Bezdetnaya L，Guillemin F.Fluorescence detection ofbladder cancer：A review.Eur Urol.2002；42(5)：417-425
Ferlay J，Steliarova-Foucher E，Lortet-Tieulent J，Rosso S，Coebergh JW，Comber H，Forman D，Bray F.Cancer incidence and mortality patterns in Europe：estimates for 40 countries in 2012.Eur J Cancer.2013 Apr；49(6)：1374-1403
Kausch I，Sommerauer M，Montorsi F，et al.：Photodynamic diagnosis innon-muscleinvasive bladder cancer：a systematic review and cumulative analysisof prospective studies.Eur Urol.Apr 2010；57(4)：595-606
Kubin A，Meissner p，Wierrani F，Burner U，Bodenteich A，Pytel A，SchmellerN.Fluorescence diagnosis of bladder cancer with new water soluble hypericinbound to polyvinylpyrrolidone：PVP-Hypericin.Photochem Photobiol.2008；84(6)：1560-1563
OlivoM，Lau W，Manivasager V，Tan PH，Soo K C，Cheng C.Macro-microscopicfluorescence of human bladder cancer using Hypericin fluorescence cystoscopyand laser confocal microscopy.Int J Oncol 2003；23(4)：983-990
Pytel A，Schmeller N.New aspect of photodynamic diagnosis of bladdertumors：fluorescence cytology.Urology 2002；59：216-219
Stenzl A，Burger M，Fradet Y，Mynderse LA，Soloway MS，Witjes JA，KriegmairM，Karl A，Shen Y，Grossman HB.Hexaminolevulinate guided fluorescence cystoscopyreduces recurrence in patients with nonmuscle invasive bladder cancer.JUrol.Nov 2010；184(5)：1907-1913
Witjes JA，Douglass J.The role of hexaminolevulinate fluorescencecystoscopy in bladder cancer.Nat Clin Pract Urol.2007Oct；4(10)：542-549
Witjes JA，Redorta JP，Jacqmin D，Sofras F，PU，Riedl C，JochamD，Conti G，Montorsi F，Arentsen HC，Zaak D，Mostafid AH，BabjukM.Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis andfollow-up of patients with non-muscle-invasive bladder cancer：review of theevidence and recommendations.Eur Urol.2010Apr；57(4)：607-614
Claims (10)
1.用于光动力学诊断的配制剂，其包含结合或复合在聚合物复合剂上的金丝桃素，其特征在于，所述金丝桃素作为盐存在。
2.根据权利要求1的配制剂，其特征在于，所述复合剂是聚乙二醇或聚-N-乙烯酰胺。
3.根据权利要求2的配制剂，其特征在于，所述聚-N-乙烯酰胺是不同聚合度和交联度的聚乙烯吡咯烷酮(PVP)。
4.根据权利要求3的配制剂，其特征在于，所述聚乙烯吡咯烷酮是PVP k17、PVP k25或PVP k30。
5.根据权利要求1至4任一项的配制剂，其特征在于，所述金丝桃素盐是碱金属盐，特别是钾盐或优选钠盐。
6.用于制备根据权利要求1至5任一项的配制剂的方法，其特征在于，将所述金丝桃素盐结合或复合到聚-N-乙烯酰胺，优选聚乙烯吡咯烷酮(PVP)上。
7.根据权利要求6的方法，其特征在于，在含水的、任选缓冲的溶液中进行复合化。
8.根据权利要求6或7的方法，其特征在于，用于静脉内、腔内、吸入、口服、腹腔内和局部施用的所述配制剂，在亲水性或疏水性载体物质中，优选以溶液、霜剂、凝胶、气溶胶的形式，乳液或作为贴剂提供。
9.根据权利要求7或8的方法，其特征在于所述含水溶液填充入注射瓶中并冻干。
10.根据权利要求1至5任一项的配制剂或根据权利要求6至9任一项的方法所获得的配制剂的用途，其用于制备光物理学或光动力学诊断和用于癌症早期识别可使用的光敏剂。
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Effective date of registration: 20200915 Address after: Neufeld, leiza, Austria Applicant after: Sano Chemicals Co.,Ltd. Address before: Austria Vienna Applicant before: SANOCHEMIA PHARMAZEUTIKA AG |
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Application publication date: 20180717 |