CN101646686A - 铁过剩症的预防或治疗剂 - Google Patents
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Abstract
本发明涉及一种铁过剩症的预防或治疗剂，该预防或治疗剂含有22β－甲氧基齐墩果－12－烯－3β，24(4β)－二醇或其药理学可接受的盐。
Description
技术领域
本发明涉及一种包含22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐的铁过剩症(Iron Overload)的预防或治疗剂。
背景技术
慢性铁过剩的特征表现为：局部或全身组织内的铁沉着增加。在组织检查中，通常称其为含铁血黄素沉着症(hemosiderosis)，但如果过剩的铁沉着伴随有组织损伤、或全身的铁达到5g以上，则称其为血色素沉着症(hematochromatosis)。(参见非专利文献1)
铁过剩症(iron overload)可按成因不同进行分类。具体而言，可大致分为：对食物中铁(食餌鉄)的吸收增加(遗传性血色素沉着症、慢性肝疾病、迟发性皮肤卟啉症(porphyria cutanea tarda)、无运铁蛋白血症、口服含铁剂的过度给药等)、由非口服给药引起的铁过负荷(由输血引起的铁过剩、静脉注射用含铁剂的过度给药等)以及上述两种情况所引发的疾病(遗传性酪氨酸血症、脑-肝-肾综合征(Zellweger氏综合征)、新生儿血色素沉着症、特发性肺含铁血黄素沉着症(idiopathic pulmonary hemosiderosis)、肾含铁血黄素沉着症(Renal hemosiderosis)等)。作为先天性疾病，常见的有特发性血色素沉着症及地中海贫血症(thalassemia)。在后天性疾病中，可列举因静脉注射用含铁剂的过度给药或输血而引起的铁过剩。(参见非专利文献2)
如果铁过剩症继续恶化，将会给以肝、心脏、胰脏为中心的内脏器官造成损伤，进一步演变为致死的病情。作为一般症状，可列举：整个体内的贮铁量的增加，心脏、胰脏、肝脏及其它器官的实质细胞(parenchymal cell)中铁蛋白及含铁血黄素形式的铁的大量沉着、以及对沉着有过剩铁的器官及部位的形态上及功能上的障碍。例如，作为针对输血后铁过剩症的治疗药物，常见的为铁螯合剂的注射药物。可是，由于该药物是注射药物，不连续多日长期给药，难以显示效果，因而不适用于对门诊类患者给药，因此，最近，对可进行口服给药的铁螯合剂的开发得到了发展。基于上述背景，期待开发出一种可有效针对铁过剩症、且无副作用的药物。
另一方面，22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇是以下述结构表示的化合物，已知其是一种具有肝细胞损伤抑制效果、且安全性高的化合物(参见专利文献1、2)。
[化学式1]
专利文献1：国际公开第97/03088号小册子
专利文献2：专利第3279574号说明书
非专利文献1：Mark H.Beers等2人(著)，福島雅典(译)，「メルクマニユアル第17版日本語版(日文版)」(The Merck Manual，17th Edition，InJapanese)，日経BP社(Nikkei BP公司)，1999年12月10日，p.883-885
非专利文献2：高橋正昭，“输血后铁过剩症和口服铁螯合剂”(「輸血後鉄過剰症と経口鉄キレ一ト剤」)，最新医学，2006年3月，61卷，3号，p.453-457
发明内容
发明要解决的问题
本发明人为解决上述问题，针对对铁过剩症的预防或治疗有效的药物进行了深入研究，结果发现，通过施用22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇，可以使血清铁蛋白值减少，因而可得到对上述铁过剩症的预防或治疗优异的药物组合物，并由此完成了本发明。
解决问题的方法
即，本发明涉及下述要点：
[1]一种铁过剩症的预防或治疗剂，其含有22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐；
[2]根据[1]的预防或治疗剂，其中，铁过剩症是血色素沉着症；
[3]22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐在制备铁过剩症的预防或治疗剂中的用途；
[4]根据[3]的用途，其中，铁过剩症是色素沉着症；
[5]用于预防或治疗铁过剩症的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐；
[6]根据[5]的化合物，其中，铁过剩症是血色素沉着症；
[7]一种预防或治疗铁过剩症的方法，该方法包括对有必要进行铁过剩症的预防或治疗的对象施用有效量的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐；
[8]根据[7]的方法，其中，铁过剩症是血色素沉着症。
发明的效果
本发明的预防或治疗剂通过施用22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐，可获得对铁过剩症的高度预防或治疗效果。
附图说明
图1是示出在口服给药22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇(50mg，200mg/日)后血清铁蛋白值的演变(平均值)的图。
图2是示出在口服给药22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇(50mg，200mg/日)后血清铁蛋白值的演变(中值)的图。
发明的具体实施方式
本说明书中的所述“铁过剩症”，是指沉积铁(貯蔵鉄)及血清铁处在高于正常值的状态。作为本发明的铁过剩症的具体实例，可列举局部性含铁血黄素沉着症、遗传性血色素沉着症、继发性含铁血黄素沉着症、继发性血色素沉着症以及原因不明的铁过剩(由肝实质性疾病、非酒精性脂肪肝及慢性丙型肝炎引发的贮铁量增加)等，优选列举血色素沉着症。
本说明书中的所述“血色素沉着症”，是指过剩的铁沉着伴有组织损伤、或全身的铁达到5g以上。血色素沉着症包括遗传性铁过剩症及非遗传性铁过剩症。所述的非遗传性铁过剩症是由因输血引起的铁过剩或因红血球生成障碍引起的铁的利用降低而引发的铁过剩症，因而也被称为继发性血色素沉着症。血色素沉着症以铁代谢的异常，摄取的铁的吸收过剩，铁结合蛋白的饱和，特别是肝脏、胰脏、皮肤中的含铁血黄素的沉着为特征。可能引发肝硬变、糖尿病(青铜色糖尿病)、皮肤色素沉着(青銅肌)，末期可能引发心功能不全。在口服或非口服地摄取大量铁的情况下或进行大量输血的情况下也会发生(ステツドマン医学大辞典第4版1998メジカルビユ一社(Stedman′s Medical Dictionary，4th Edition，1998，Medical View Co.，Ltd.))。
用作本发明的预防或治疗剂的有效成分的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇为公知化合物，可利用例如WO97/03088号小册子的实施例22(化合物27)中记载的方法获得。22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇可通过与制药学可接受的碱作用而简单地成盐。作为优选的碱，可列举氢氧化钠、氢氧化钾、氢氧化铝、碳酸钠、碳酸钾及碳酸氢钠等无机碱，以及哌嗪、吗啉、哌啶、乙胺及三甲胺等有机碱。
22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐通常可以以例如胶囊、微胶囊、药片、颗粒、细粒、粉末等常用的药剂形式口服给药。另外，也可以以静脉注射、肌肉注射等注射剂等常用的药剂形式非口服给药(例如，静脉注射、肌肉注射、皮下给药、腹腔内给药、直肠给药、经皮给药)。上述各种制剂可通过使用常用的赋形剂、增容剂(extender)、粘合剂、湿润剂、崩解剂、表面活性剂、润滑剂、分散剂、缓冲剂、保存剂、助溶剂、防腐剂、矫味矫臭剂、镇痛剂、稳定剂等，利用常规方法制成。作为可用的无毒性的上述添加剂，可列举例如乳糖、果糖、葡萄糖、淀粉、明胶、碳酸镁、合成硅酸镁、滑石、硬脂酸镁、甲基纤维素、羧甲基纤维素或其盐、阿拉伯树胶、聚乙二醇、糖浆、凡士林、甘油、乙醇、丙二醇、柠檬酸、氯化钠、亚硫酸钠、磷酸钠等。如上所述，22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐可以以包含药理学可接受的载体或稀释剂的药物组合物的形式给药。
对于本发明的预防或治疗剂中22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇的剂型、给药方法、给药量、给药期间等，可以根据例如患者的体重、年龄、症状程度等而适当设定。例如，可以每日1次或分多次地口服或非口服给药1～1000mg。优选每日分2次口服或非口服给药25～800mg。
作为对铁过剩症的诊断有用的检查结果，已知有血清铁蛋白值、血清铁、总铁结合力(TIBC)等。随着铁负荷量增加，血清铁蛋白值会成比例地增加。由于使用血清铁蛋白值和肝MRI来监视铁过剩症的方法简便、并且对患者造成的负担也小，因而推荐采用(最新医学61卷，3号，453-457，2006)。
实施例
以下，结合实施例对本发明进行详细说明，但这些实施例并不限定本发明的范围。
实施例1
以丙型慢性肝炎的患者为对象，进行了24周的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇的口服给药。作为给药量，设置了50mg/日给药组和200mg/日给药组。对每个给药组进行22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇的口服给药，每日分2次、即在早晚餐后各施用每日给药量的一半(例如：对于50mg/日给药组，每日给药2次，分别在早晚餐后口服给药25mg)。在口服给药后的2、4、8、12、16、20、24周后分别采集血清试样，测定了血清铁蛋白(血清试样采集人数：对于50mg/日给药组，2、4、8、12、16、20、24周后的血清试样采集人数分别为49人、48人、47人、44人、45人、44人、40人；对于200mg/日给药组，2、4、8、12、16、20、24周后的血清试样采集人数分别为45人、44人、43人、43人、43人、41人、39人)。血清铁蛋白值通过化学发光免疫测定法(CLIA)进行了测定[基于ChemilumiACS-ferritin II(Bayer Medical株式会社)的附属文件中记载的方法进行了测定]。
将22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇的给药前的血清铁蛋白值规定为0，以％表示每次进行血清试样采集时的血清铁蛋白值，求出了所有患者的平均值及中值。其结果分别示于图1和图2中。
由该结果可确认：通过施用22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇，可使血清铁蛋白值减少，因而可以得到对铁过剩症的预防或治疗优异的药物组合物。
工业实用性
根据本发明，可以提供一种含有22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐的铁过剩症的预防或治疗剂。
以上结合特定实施方式对本发明进行了说明，但本领域技术人员所作出的显而易见的变形或改进也包括在本发明的范围内。
Claims (8)
1.一种铁过剩症的预防或治疗剂，该铁过剩症的预防或治疗剂含有22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐。
2.根据权利要求1所述的预防或治疗剂，其中，铁过剩症是血色素沉着症。
3.22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐在制备铁过剩症的预防或治疗剂中的用途。
4.根据权利要求3所述的用途，其中，铁过剩症是血色素沉着症。
5.用于预防或治疗铁过剩症的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐。
6.根据权利要求5所述的化合物，其中，铁过剩症是血色素沉着症。
7.一种预防或治疗铁过剩症的方法，该方法包括对有必要进行铁过剩症的预防或治疗的对象施用有效量的22β-甲氧基齐墩果-12-烯-3β，24(4β)-二醇或其药理学可接受的盐。
8.根据权利要求7所述的方法，其中，铁过剩症是血色素沉着症。
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| CN109069866A (zh) * | 2016-05-06 | 2018-12-21 | 安成生物科技股份有限公司 | 治疗和/或预防与血液相关病症的方法和制剂 |
| CN113164594A (zh) * | 2018-11-20 | 2021-07-23 | 株式会社英仙蛋白质科学 | 向细胞内摄入铁的抑制剂 |
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| EP2392354A4 (en) * | 2009-01-30 | 2012-08-08 | Meiji Seika Pharma Co Ltd | FINE PULVERIZED PHARMACEUTICAL COMPOSITION |
| US10098878B2 (en) | 2014-10-10 | 2018-10-16 | The Board Of Regents Of The University Of Texas System | HIF-2α inhibitors for treating iron overload disorders |
| MX390514B (es) | 2015-10-23 | 2025-03-20 | Vifor Int Ag | Inhibidores de ferroportina novedosos |
| JOP20180036A1 (ar) | 2017-04-18 | 2019-01-30 | Vifor Int Ag | أملاح لمثبطات فروبورتين جديدة |
| TW202102478A (zh) | 2019-04-01 | 2021-01-16 | 瑞士商威佛（國際）股份有限公司 | 新穎的鐵螯合物 |
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| CN109069866A (zh) * | 2016-05-06 | 2018-12-21 | 安成生物科技股份有限公司 | 治疗和/或预防与血液相关病症的方法和制剂 |
| CN113164594A (zh) * | 2018-11-20 | 2021-07-23 | 株式会社英仙蛋白质科学 | 向细胞内摄入铁的抑制剂 |
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