CN1711079A - 作为拟甲状腺素剂的硫酸3,5,3′-三碘甲状腺原氨酸及其药用制剂 - Google Patents
作为拟甲状腺素剂的硫酸3,5,3′-三碘甲状腺原氨酸及其药用制剂 Download PDFInfo
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- XBQYQXVJBNDCGY-LBPRGKRZSA-N 3,3',5-triiodo-L-thyronine sulfate Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(OS(O)(=O)=O)C(I)=C1 XBQYQXVJBNDCGY-LBPRGKRZSA-N 0.000 claims abstract description 16
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Abstract
本发明涉及通常称为T3S的硫酸三碘甲状腺原氨酸作为具有拟甲状腺素活性的药物用于治疗三碘甲状腺原氨酸(T3)器质性缺乏所致的病症的用途,它可以为其本身,或者与甲状腺素(T4)联合使用;本发明还涉及其药用制剂。
Description
发明领域
本发明涉及硫酸3,5,3’-三碘甲状腺原氨酸在治疗3,5,3’-三碘甲状腺原氨酸器质性缺乏所致病症中的应用,它通常称为硫酸三碘甲状腺原氨酸或者硫酸T3,或者称为T3S更好,它充当活性成分,可单独使用,或者与甲状腺素联合使用。
发明背景
大量碘甲状腺原氨酸存在于血中,它们是由甲状腺直接生成的,或者是其它碘甲状腺原氨酸外周代谢的结果。其中,3,5,3′-三碘甲状腺原氨酸(首字母缩略词T3)被认为是甲状腺激素(TH)的生物活性形式,因为它对甲状腺激素特异受体显示出高度亲和性,而且正常情况下其在血清中的浓度足以活化所述受体。
健康成人甲状腺主要分泌产物是甲状腺素,通常称为首字母缩略词T4。I型和II型5’-碘甲状腺原氨酸单脱碘酶(分别称为I型MD和II型MD)均可将它在外周转化为它的生物活性形式T3(参考文献1),这是通过酶切除该分子外芳环上碘原子而进行的。这种代谢途径是T3内源性产生的主要机制;因此,可适当地将T4看作是一种激素原。另一方面,甲状腺也可直接分泌较小部分的T3。平均而言,体重70Kg的成人每天产生的T4量为100μg,而T3的总产生量约为25μg。此25μg T3中的4-8μg由甲状腺直接分泌,其余部分来源于T4的外周转化。
T3具有2种不同的代谢途径。主要代谢途径在于III型5-碘甲状腺原氨酸单脱碘酶(III型MD)对内芳环的部分脱碘作用,而获得3,3′-二碘甲状腺原氨酸,它在生物学上是无活性的,而且通过脱碘或硫酸结合作用将被进一步代谢。另一种代谢途径涉及机体产生的T3总量的约20%,并引起T3的硫酸结合,而获得T3S,T3S不能与甲状腺激素结合(参考文献2),因此在生物学上是无活性的(参考文献3)。
与T3上所发生的不同,T3S不被III型MD脱碘,而是I型MD的良好底物(参考文献4),I型MD可将它很快地转化为硫酸3,3′-二碘甲状腺原氨酸。因此,已经广泛地达成共识,在健康成人中,T3的硫酸结合而获得T3S是加速T3分解代谢的一种途径,这样可促进其胆汁和泌尿排泄。实际上,发现健康成人T3S的血清水平在生理上是低的,而当I型MD活性下降时其水平较高。
然而,还意外地发现,仅在身体某些区域和器官中存在硫酸酯酶,所述硫酸酯酶在特定生理条件和状况下能够将T3S再转化为它的活性形式T3(参考文献7-9)。
这些酶据描述在肠道微菌群以及机体组织中,比如肝、肾和中枢神经系统(参考文献10)。
最近已经发现,宫内生长期间血清中内源性T3S水平相当高,而且这种情况由机体保持,即高于成人正常情况下的水平,至少一直到产后的第四个月(参考文献11)。鉴于甲状腺激素在生长过程中所起到的重要作用,特别是对中枢神经系统功能来说,对其可能性的推测是,在生命的第一阶段,如果需要和当需要时,在这种组织中,T3S也可能被机体用作T3的一种偶然来源。对死后人神经脑组织尸检标本进行的研究显示,其中的T3量受到III型MD的限制(参考文献12)。尽管这种酶不攻击T3S,推测T3S可例外地代表含有硫酸酯酶的那些组织中T3激素可替代的内源性来源,如果在这些组织中特别需要此激素时,这些硫酸酯酶能将T3S转化为其活性形式(参考文献8,13)。
已进行了进一步的研究,以确定甲状腺激素生成和代谢过程中T3S所起的有效作用。最近这些研究表明在甲状腺机能减退大鼠(参考文献10)以及甲状腺机能正常大鼠(参考文献14)中它显示出拟甲状腺素作用。在这两种情况中,T3S已经表现出其效力约为T3的1/5。另外,应用T3S和T3处理均引起甲状腺机能正常大鼠促甲状腺激素(TSH)血清水平明显下降,由此表明在抑制其分泌方面,它们具有相似的能力。相反,在甲状腺机能减退大鼠中,在抑制TSH分泌方面,与T3相比,T3S的能力较差。众所周知TSH是甲状腺机能状态高度敏感的指标,而且允许检测其激素分泌最小的变动。实际上,在甲状腺机能减退情况下其水平较高,甚至是定义为亚临床的那些条件下,而当存在过量的甲状腺激素时,它们将减少。因此,就抑制TSH形成的能力而言,T3S似乎出乎意料地不能与T3相比。
总之,特别是鉴于最新的研究,目前仍未清楚彻底地了解T3S所发挥的生物学作用。
事实上,其主要的、有充分根据的并且普遍公认的特征是它的非生物学活性,亦即它是T3的生物学无活性代谢产物(参考文献2和3),而且这种硫酸化途径被认为是T3分解代谢的代谢活化剂(参考文献5)。
另一方面,仅仅在特定组织中,并在异常的临界条件下,由于在那些组织中缺乏甲状腺激素,它显示出充当T3内源性局部来源的潜能。
结果,今天熟练技术人员仍将面对复杂而且具有几分矛盾的状况,此状况仅仅突出了这种产物的某些生物学特性,而在深入研究中需要更加详尽。
无论如何,形成现有技术的几个文件中,没有一个表明或提出在治疗中应用T3的这种不规则代谢产物的可能性。接近的现有技术文件,无论是实验性质的文件,还是基本上推测的文件,无论是单独采用,还是与其它相关文件联合采用,都没有提出这种用途,或者甚至是T3S用作药物的潜在用途,不论是应用其本身,还是优选与其它甲状腺激素或激素原例如T4联合使用。仅在机体的某些特殊组织中,并在特定的特殊条件下,部分T3S可被再转化为T3,此事实并不意味、也不暗示、也不提示:通过外源性地施用这种产物,可将这种特性推广到整个有机体。特别是,没有提到,口服应用这种产物,甚至是按照制药技术中已知方法以保护形式应用这种产物,可使其成为生物可利用的,这也是由于众所周知在那些没有适宜硫酸酯酶存在的区域中,这种产物将会被快速代谢,并通过胆汁和尿液被排泄掉。
发明概述
现在意外地发现,T3S,其本身或者与其它甲状腺激素或激素原联合(优选与T4联合),并且按照所需应用适当制备,特别可用作一种药物,此药物可用于治疗机体活性甲状腺激素(特别是T3)需要量产生不足而引起的所有病症,这点是本发明的一个方面。
发明详细描述
事实上已意外地发现,应用T3S可使体内T3水平长时间(12-18小时)保持稳定,这与其正常代谢中已知的情况相反,而且此结果可特别用于需要补充最具活性形式甲状腺激素的那些情况。
T3S与T4联合应用特别优选用于甲状腺机能减退的治疗,而且这是本发明的主要方面。T4与T3联合代表这样的激素联合:理论上这样可更精确地模拟正常甲状腺的分泌。事实上,已经尝试生产了含有上述两种碘甲状腺原氨酸的药物组合物,其配制比例与正常生理分泌相似,而且它们已经上市。不幸的是,同时口服给予T4和T3并不能再现正常的甲状腺激素血清水平,这是由T3的药物动力学造成的。事实上,T3的吸收很快,而且在口服给药后排泄也同样很快;其排泄速率约比T4高20倍。由于此原因,如果与正常生理水平相比,应用T3可使激素浓度出现危险的峰值过高,然后是太快地下降到生理水平之下。因此,目前大多数专科医生宁愿单独使用T4,即使在此方法中T3的产生仅仅依赖于T4的外周脱碘作用,因为甲状腺不直接分泌T3,或者直接分泌的T3严重不足。
相反,本发明的联合应用避免了上述难题,因为已意外地发现,例如在口服给药后,T3S使T3血清水平逐渐升高,并长时间保持稳定,因此防止形成太高的峰值。
在应用T3S治疗T3器质性缺乏引起的病症时,另一个意外的优势是其最近发现的全身性拟甲状腺素活性,连同较小抑制TSH的分泌。甲状腺癌患者接受甲状腺切除后,这种作用特别有用,此时由于进行全身闪烁照相检查,必须暂停T4给药。在这种情况中,应用T3S替代T4可解决患者的需求,而且不干扰诊断检查。
T3S治疗甲状腺机能减退的另一个优势涉及其自限能力。事实上,I型MD对它进行有效的脱碘,就I型MD而言,甲状腺激素对其起刺激作用。在甲状腺机能减退的患者中,I型MD活性下降;因此,也减慢了T3S的消除。事实上,它对机体的作用增大。相反,过度给药后,I型MD活性增强,因此使T3S消除增多,即限制了可能的不良副作用。
最后但相当重要的是,T3S的另一个优势是,它是机体中正常存在的一种代谢产物,通常它是无活性的,即是无毒的。因此,其应用后出现过敏或不耐受性的问题不是有理由可预测到的。
因此,本发明的另一个主要方面涉及包含T3S作为活性成分的药用制剂,在此制剂中T3S为其本身或者与其它甲状腺激素或激素原联合。特别优选的是包含T3S与T4联合的制剂。
根据所需的给药类别,上述制剂在活性成分的剂量上不同,或者在药用形式的类型上不同。而且它们还可含有有用的添加剂,诸如制药技术中常用的赋形剂、稀释剂、溶解剂、溶剂、载体、染料、调味剂、增甜剂。对于特定应用需要,具体药用制剂的制备清楚地包括在本发明的一般技术领域中。
实验部分
例如,可口服应用T3S,其剂量为5-1000μg,优选为10-500μg,更优选25-250μg,此对熟练技术人员绝对没有任何限制。
类似地,当与T4联合应用时,T3S的剂量优选为10-500μg,T4的剂量优选为10-250μg,T3S更优选的剂量为25-250μg,T4更优选的剂量为25-200μg。
两种代表性的口服给药的制剂是从众多优选制剂中挑选出来的,下文中将它们作为实施例。显然,所述制剂对其它可能的改变没有限制,根据具体药理学应用或特定病症,这些改变也可包括不同形式的给药、不同的剂量或不同的组分。
实施例A)-含有T3S的口服制剂
T3S 50μg;
无水磷酸氢钙 103.5mg;
Mais淀粉 17.65mg;
微晶纤维素 5mg;
羧甲基酰胺钠 5mg;
滑石 5mg;
柠檬酸 2.8mg;
硬脂酸镁 1mg
实施例B)-含有T3S和T4的口服制剂
T3S 50μg;
T4钠盐 125μg;
无水磷酸氢钙 103.5mg;
Mais淀粉 17.525mg;
微晶纤维素 5mg;
羧甲基酰胺钠 5mg;
滑石 5mg;
柠檬酸 2.8mg;
硬脂酸镁 1mg
特别是,当进行联合应用时,本发明的制剂也可能包括分别单独配制剂量的T3S和T4,这样可进行序贯给药。在这种情况下,可使用一种适宜的药盒,它可以使所述活性成分进行不同的给药,这样根据所需的治疗应用,不同患者的方法可以不同。在这种情况下,专科医生可根据患者的实际需要,在处方调整方面具有广泛的选择余地。
作为非限制性实施例,在口服给药情况下,一个包装上含有两个独立泡孔可符合期望的范围,这两个泡孔可具有不同的形状和/或颜色和/或不同的内容和/或剂量。还存在其它可能性,而且这些可能性对于本领域的专家来说是容易获得的。
本发明的药用组合物可用于治疗三碘甲状腺原氨酸(T3)器质性缺乏而引起的病症,例如自身免疫性甲状腺疾病所致的原发甲状腺机能减退、激素产生缺陷、甲状腺切除术、先天性甲状腺机能减退,以及I型5’-碘甲状腺原氨酸单脱碘酶(I型MD)活性下降所致的某些疾病,这种I型MD活性下降例如是由甲状腺机能减退、非甲状腺全身性疾病、禁食、硒缺乏等引起的。
参考文献
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Claims (16)
1、硫酸三碘甲状腺原氨酸用作药物。
2、按照权利要求1的硫酸三碘甲状腺原氨酸用作药物,它具有拟甲状腺素活性。
3、按照权利要求2的硫酸三碘甲状腺原氨酸,它用于治疗三碘甲状腺原氨酸器质性缺乏所致的病症。
4、按照权利要求3的硫酸三碘甲状腺原氨酸,其中所述病症包括自身免疫性甲状腺疾病所致的原发甲状腺机能减退、激素产生缺陷、甲状腺切除术、先天性甲状腺机能减退。
5、按照权利要求2的硫酸三碘甲状腺原氨酸,它用于治疗I型5’-碘甲状腺原氨酸单脱碘酶活性下降所致的疾病。
6、按照权利要求5的硫酸三碘甲状腺原氨酸,其中所述I型5’-碘甲状腺原氨酸单脱碘酶活性下降包括甲状腺机能减退、非甲状腺性全身性疾病、禁食、硒缺乏,这些均在其范围内。
7、药用组合物,它包含用作活性成分的硫酸三碘甲状腺原氨酸。
8、按照权利要求7的药用组合物,其中所述硫酸三碘甲状腺原氨酸与甲状腺素联合配制。
9、按照权利要求7和8的药用组合物,其中所述组合物还包括添加剂,象赋形剂、稀释剂、溶解剂、溶剂、载体、染料、调味剂、增甜剂。
10、按照权利要求7的药用组合物,其中硫酸三碘甲状腺原氨酸的给药剂量为5-1000μg。
11、按照权利要求10的药用组合物,其中硫酸三碘甲状腺原氨酸的给药剂量为10-500μg。
12、按照权利要求10的药用组合物,其中硫酸三碘甲状腺原氨酸的给药剂量为25-250μg。
13、按照权利要求8的药用组合物,其中所述联合应用的给药剂量是硫酸三碘甲状腺原氨酸为10-500μg,甲状腺素为10-250μg。
14、按照权利要求8的药用组合物,其中所述联合应用的给药剂量是硫酸三碘甲状腺原氨酸为25-250μg,甲状腺素为25-200μg。
15、一种药盒,用于按照权利要求8、9和11至14的药用组合物的区分给药或序贯给药。
16、硫酸三碘甲状腺原氨酸用于制备按照权利要求7至15的药用组合物的用途。
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AU (1) | AU2003292006A1 (zh) |
CY (1) | CY1107312T1 (zh) |
DE (1) | DE60308718T2 (zh) |
DK (1) | DK1560575T3 (zh) |
ES (1) | ES2273045T3 (zh) |
IT (1) | ITMI20022394A1 (zh) |
PT (1) | PT1560575E (zh) |
WO (1) | WO2004043452A1 (zh) |
Cited By (4)
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CN103534232A (zh) * | 2011-04-08 | 2014-01-22 | 伯拉考成像股份公司 | 用于制备3,5-二碘-o-[3-碘苯基]-l-酪氨酸的硫酸化衍生物的方法 |
US9012438B2 (en) | 2002-11-13 | 2015-04-21 | Aldo Pinchera | 3,5,3′ -triiodothronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
US9890116B2 (en) | 2002-11-13 | 2018-02-13 | Bracco Imaging S.P.A. | Process for the preparation of a sulfated derivative of 3,5-diiodo-O-[3-iodophenyl]-L-tyrosine |
CN112437812A (zh) * | 2018-07-13 | 2021-03-02 | 埃吉尔比奥公司 | 用于诊断甲状腺功能异常的生物传感器 |
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GB0525461D0 (en) | 2005-12-15 | 2006-01-25 | Archimedes Dev Ltd | Pharmaceutical compositions |
US20120178813A1 (en) | 2011-01-12 | 2012-07-12 | Thetis Pharmaceuticals Llc | Lipid-lowering antidiabetic agent |
CN102507919A (zh) * | 2011-11-08 | 2012-06-20 | 江苏省原子医学研究所 | 一种标记3,3’-二碘甲腺氨酸硫酸化物的方法及检测试剂盒 |
CA2947741A1 (en) | 2014-05-05 | 2015-11-12 | Thetis Pharmaceuticals Llc | Compositions and methods relating to ionic salts of peptides |
US9242008B2 (en) | 2014-06-18 | 2016-01-26 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of fatty acids |
JP2017526623A (ja) | 2014-06-18 | 2017-09-14 | テティス・ファーマシューティカルズ・エルエルシー | 活性物質のミネラル・アミノ酸錯体 |
WO2017210604A1 (en) | 2016-06-03 | 2017-12-07 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators of inflammation |
JP6968603B2 (ja) * | 2017-07-10 | 2021-11-17 | キヤノン株式会社 | 画像形成装置、画像形成方法、プログラム |
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-
2002
- 2002-11-13 IT ITMI20022394 patent/ITMI20022394A1/it unknown
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2003
- 2003-11-11 CN CNA2003801030574A patent/CN1711079A/zh active Pending
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- 2003-11-11 PT PT03767529T patent/PT1560575E/pt unknown
- 2003-11-11 EP EP20060117480 patent/EP1767202A1/en not_active Withdrawn
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- 2003-11-11 EP EP03767529A patent/EP1560575B1/en not_active Expired - Lifetime
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- 2003-11-11 WO PCT/EP2003/012584 patent/WO2004043452A1/en active IP Right Grant
- 2003-11-11 AU AU2003292006A patent/AU2003292006A1/en not_active Abandoned
- 2003-11-11 US US10/532,447 patent/US9012438B2/en not_active Expired - Fee Related
- 2003-11-11 ES ES03767529T patent/ES2273045T3/es not_active Expired - Lifetime
- 2003-11-11 DE DE2003608718 patent/DE60308718T2/de not_active Expired - Lifetime
- 2003-11-11 AT AT03767529T patent/ATE340570T1/de active
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- 2013-01-31 US US13/755,279 patent/US9044441B2/en active Active
- 2013-06-13 US US13/916,710 patent/US9468619B2/en active Active
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9012438B2 (en) | 2002-11-13 | 2015-04-21 | Aldo Pinchera | 3,5,3′ -triiodothronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
US9044441B2 (en) | 2002-11-13 | 2015-06-02 | Bracco S.P.A. | 3,5,3′-triiodothyronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
US9468619B2 (en) | 2002-11-13 | 2016-10-18 | Bracco S.P.A. | 3,5,3′-triiodothyronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
US9890116B2 (en) | 2002-11-13 | 2018-02-13 | Bracco Imaging S.P.A. | Process for the preparation of a sulfated derivative of 3,5-diiodo-O-[3-iodophenyl]-L-tyrosine |
US10238615B2 (en) | 2002-11-13 | 2019-03-26 | Bracco S.P.A. | 3,5,3′-triiodothyronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
CN103534232A (zh) * | 2011-04-08 | 2014-01-22 | 伯拉考成像股份公司 | 用于制备3,5-二碘-o-[3-碘苯基]-l-酪氨酸的硫酸化衍生物的方法 |
US10457635B2 (en) | 2011-04-08 | 2019-10-29 | Bracco Imaging S.P.A. | Process for the preparation of a sulfated derivative of 3,5-diiodo-o-[3-iodophenyl]-l-tyrosine |
CN112437812A (zh) * | 2018-07-13 | 2021-03-02 | 埃吉尔比奥公司 | 用于诊断甲状腺功能异常的生物传感器 |
Also Published As
Publication number | Publication date |
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JP5301074B2 (ja) | 2013-09-25 |
WO2004043452A1 (en) | 2004-05-27 |
DE60308718T2 (de) | 2007-08-02 |
EP1767202A1 (en) | 2007-03-28 |
ITMI20022394A1 (it) | 2004-05-14 |
DE60308718D1 (de) | 2006-11-09 |
EP1560575B1 (en) | 2006-09-27 |
US20130281536A1 (en) | 2013-10-24 |
US20050272816A1 (en) | 2005-12-08 |
US9468619B2 (en) | 2016-10-18 |
JP2006508956A (ja) | 2006-03-16 |
US9044441B2 (en) | 2015-06-02 |
US20110245342A1 (en) | 2011-10-06 |
US20170007563A1 (en) | 2017-01-12 |
US10238615B2 (en) | 2019-03-26 |
US9012438B2 (en) | 2015-04-21 |
ES2273045T3 (es) | 2007-05-01 |
DK1560575T3 (da) | 2007-01-29 |
ATE340570T1 (de) | 2006-10-15 |
CY1107312T1 (el) | 2012-11-21 |
AU2003292006A1 (en) | 2004-06-03 |
CN101406467A (zh) | 2009-04-15 |
PT1560575E (pt) | 2007-01-31 |
JP2011102306A (ja) | 2011-05-26 |
EP1560575A1 (en) | 2005-08-10 |
US20130146502A1 (en) | 2013-06-13 |
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