CN1270027A - 一种酞胺哌啶酮衍生物的稳定水溶液 - Google Patents

一种酞胺哌啶酮衍生物的稳定水溶液 Download PDF

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CN1270027A
CN1270027A CN00102595A CN00102595A CN1270027A CN 1270027 A CN1270027 A CN 1270027A CN 00102595 A CN00102595 A CN 00102595A CN 00102595 A CN00102595 A CN 00102595A CN 1270027 A CN1270027 A CN 1270027A
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T·格尔曼
H·库格尔曼
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Abstract

本发明描述了EM12水溶液,该水溶液适用于非肠道应用形式,特别适用于将EM12以静脉内形式应用于治疗免疫学和血液学－肿瘤学疾病;本发明还描述了制备相应EM12溶液的方法。

Description

一种酞胺哌啶酮衍生物的稳定水溶液
本发明涉及酞胺哌啶酮衍生物EM12的非肠道应用形式以及制备酞胺哌啶酮衍生物EM12的方法。这种应用形式可用于治疗炎性和血液学-肿瘤学疾病。
由噬菌细胞(如单细胞)引起的原炎性胞质TNF-α(肿瘤坏死因子)和白介素(IL)-12的过量生成，在各种炎性疾病的发病机理中起着重要的作用(Trinchieri 1995，Ann.Rev.Immunol。13：251)。
治疗这类疾病的一种方法包括，服用免疫调节活性成分以有意识抑制这些原炎性胞质的生成，所述免疫调节活性成分包括如地塞米松或酞胺哌啶酮或酞胺哌啶酮衍生物EM12。而肾上腺皮质类脂醇(如地塞米松)以注射液形式存在，迄今为止还没有注射液形式的衍生物EM12，所述衍生物EM12具有免疫调节作用。DE 197 43 968.3中提出了酞胺哌啶酮的非肠道应用形式。
酞胺哌啶酮已被证明优于用于治疗几种口糜的传统免疫抑制剂。其中酞胺哌啶酮可在不导致一般性免疫抑制的情况下，显示出具有优良效力的疾病的其他实例包括皮肤性红斑狼疮、坏疽性脓皮病和Bechet’s综合症中的泌尿生殖系统溃疡，以及由HIV感染的溃疡症，这种溃疡症在组织上与口疮性溃疡并没有什么不同，而与多数HIV-相关的粘膜与皮肤损害不同，在该溃疡症中测定不出微生物病原体。由于与口糜不同，有时也可呈现出主要口疮尺寸的这种损害可能会存在于整个消化道中，当其位于咽腔或食道中时，它们会使得食物的摄取不同，而且由于其造成的疼痛不同，而使得口服药物的摄取不同。
在其中口服摄取变得不同或者甚至不能口服摄取的咽喉或食管严重溃疡的情况下，以及在其中严重症状使得口服摄取变得不可预测的与HIV-相关的病理学情况下，非肠道给药可以提供解决问题的方法。但是，酞胺哌啶酮在水中的低溶解度(Arch.Pharm.321，371(1988))形成了该活性成分的非肠道给药的障碍。由此并不缺乏试图研制水溶性应用形式的努力。水溶性酞胺哌啶酮衍生物是从DE 42 11812中得知的，该衍生物的水中溶解度显示出比酞胺哌啶酮的水中溶解度高得多且适用于非肠道应用。
而且，人们已经建议将酞胺哌啶酮前药应用于非肠道应用，所述前药可在生理pH范围内，以水溶液形式给药，且无毒害(DE 196 13976)。存在的缺点是，制备上述两种类型的化合物的成本远高于制备酞胺哌啶酮的成本。
关于其在含水介质中的溶解度及经历自发水解的趋势，由于酞胺哌啶酮衍生物EM12显示出与酞胺哌啶酮类似的不良性能，所以本发明的潜在目的在于研制这种具有免疫调节作用的酞胺哌啶酮衍生物的水溶性应用形式。进一步的目的是所研制的应用形式应当在其水合溶解形式下稳定，而且应当没有可能导致毒物学作用的生理学不相容的物化性能。
已经发现，由于EM12具有经历自发水解的趋势，所以生产水溶液是行不通的。然而，当水溶液的pH值降至小于或等于5.5的pH范围时，水解将不会发生。
         表1.  酞胺哌啶酮和EM12物质的结构
由此，本发明涉及适用于非肠道应用的，pH小于5.5的水溶液且包含作为构成成分葡萄糖的EM12溶液。根据本发明，EM12以外消旋物或以对映体之一的形式溶解在等渗葡萄糖溶液中。这种类型的溶液可用于非肠道应用，特别适用于静脉内应用。
EM12具有活性组分含量至少0.2mg/ml的应用形式适合于可注射应用形式。
本发明进一步涉及所述水溶液的制备方法。根据本发明，将EM12加入到pH为4至5的等渗葡萄糖溶液中，震荡该混合物，直至EM12完全溶解和/或为了缩短制备时间，接着利用超声波处理，再在无菌条件下过滤。
不论是以快速注入形式给药，还是以慢速注入形式给药(10ml/min)，本发明的应用形式均是没有毒害的。
除了EM12之外，本发明的药物还包含葡萄糖。其他辅助性物质也可任意地加入到EM12溶液中去。所述的进一步辅助物质及其所使用的量确切地取决于药物如何进行给药。
对患者进行给药的活性成分的量取决于患者的体重、疾病的迹象和严重程度，通常为0.1至1mg/kg。
非肠道EM12溶液也可用作罐装酞胺哌啶酮溶液，用于治疗其中发病机理是过多生成TNF-α和JL-12的疾病(还包括肠疾病、皮肤疾病、粘膜疾病和脉管疾病，以及自身免疫性疾病)。进一步地，由于其抗血管遗传作用，它们也可用于治疗血液学疾病和其它肿瘤学疾病。
上述疾病还包括：皮肤性炎症(如非典型皮炎、牛皮癣、湿疹)、呼吸道炎症(如支气管炎、肺炎、支气管哮喘、ARDS(成年人呼吸窘迫综合症)、肉状瘤病、硅肺炎/纤维症)、胃肠道炎症(如胃与十二指肠溃疡、Crohn’s疾病、溃疡性结肠炎)，还包括其它疾病，如肝炎、胰腺炎、阑尾炎、腹膜炎、肾炎、口疮病、结膜炎、角膜炎、眼色素层炎、鼻炎。
免疫性疾病包括如：关节炎类疾病(如类风湿性关节炎、与HLA-B27相关的疾病)，也包括多发性硬化症、幼稚型糖尿病和红斑狼疮。
进一步的症状包括：脓毒病、细菌性脑膜炎、萎靡不振、拒绝移植反应和移植物抗宿主反应，以及多次输液综合症和动脉粥样硬化。
可以治疗的其它疾病包括：血液学疾病，如多发性骨髓瘤和白血病，以及其它肿瘤学疾病，如成胶质细胞瘤、前列腺癌和肝癌。
实施例
为了制备浓度为200μg/ml的注射液，将于用于注射的350ml 3％葡萄糖溶液(pH4至5)中的70mg外消旋EM12引入到玻璃输液瓶中。彻底震荡混合物，利用超声波处理15分钟。由于溶解EM12的浓度取决于震荡强度，也取决于超声波处理，所以可重复这两种步骤，直至得到完全溶解。超声波浴中的水温最高可达33℃。在无菌条件下，利用孔径为0.22μm(Millipore S.A.，Molsheim，法国)的Millex GS消毒过的过滤器，将溶液过滤到无菌注射瓶中。溶液在室温下存放。
最终溶液的pH为5.5。
                稳定性测试
在2周时间内，将数份溶液重复用作分析样品。
在2周后，EM12仍然存在且保持其完整的生物药效力。
              免疫调节效力测试
为了研究所制备的溶液的免疫调节效力，从末梢血液单核细胞(PBMCs)中分离出人道单核细胞，利用细菌性LPS(脂多糖)活化。通过夹心ELISAs(Biosource Europe，Fleurus，比利时)的方式，测定从细胞培养液得到的上清液中的TNF-α和IL-12的浓度。
        表2.由上述实施例制得的EM12溶液
对LPS-活化单核细胞的TNF-α和IL12生成的影响
      pg/ml  ％inh*     EM 1210μg/mlpg/ml  ％inh*     EM 122μg/mlpg/ml  ％inh*
    TNF-α  23678    0  9548    61  9915    60
    IL-12  2534     0   464    79   528    74
*％inh.＝在没有抑制剂的对照组中，抑制TNF-α和IL 12生成的百分数％

Claims (3)

1.根据专利申请DE 197 43 968.3的，包含用于非肠道给药的EM12的稳定水溶液，其中EM12溶解于等渗葡萄糖溶液中，且溶液的pH小于或等于5.5。
2.根据权利要求1的稳定水溶液，其特征在于该稳定水溶液含有含量至少为0.2mg/ml的活性成分。
3.制备权利要求1的稳定水溶液的方法，其特征在于将EM12加入到pH为4至5的等渗葡萄糖溶液中，震荡该混合物，直至完全溶解和/或为了缩短制备时间，接着利用超声波处理，再在无菌条件下过滤。
CN00102595A 1999-03-31 2000-03-30 一种酞胺哌啶酮衍生物的稳定水溶液 Pending CN1270027A (zh)

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DE19914621A DE19914621C2 (de) 1997-10-06 1999-03-31 Stabile wässrige Lösung von EM 12
DE19914621.7 1999-03-31

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CN1270027A true CN1270027A (zh) 2000-10-18

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US7268148B2 (en) * 1999-05-20 2007-09-11 Regents Of The University Of Michigan Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes
DE19957342A1 (de) * 1999-11-29 2001-05-31 Gruenenthal Gmbh Verfahren zur Behandlung und/oder Prophylaxe von IL-12-bedingten Erkrankungen
JP4361273B2 (ja) 2001-02-27 2009-11-11 アメリカ合衆国 潜在的な血管形成阻害剤としてのサリドマイド類似体
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US8952895B2 (en) 2011-06-03 2015-02-10 Apple Inc. Motion-based device operations
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NO20001658D0 (no) 2000-03-30
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AU766250B2 (en) 2003-10-09
AU2420400A (en) 2000-10-05
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PL339336A1 (en) 2000-10-09
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US6306879B1 (en) 2001-10-23
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AR023199A1 (es) 2002-09-04
PE20001597A1 (es) 2001-01-20
SI1040838T1 (en) 2003-08-31
DE50001522D1 (de) 2003-04-30
SK4632000A3 (en) 2000-10-09
JP2000290180A (ja) 2000-10-17
IL135340A0 (en) 2001-05-20
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CA2302886A1 (en) 2000-09-30
CO4970704A1 (es) 2000-11-07
ZA200001618B (en) 2000-10-25
HK1033645A1 (en) 2001-09-14
NZ503428A (en) 2001-08-31

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