CN1092962C - 一种减轻骨及骨关节疾病疼痛的药物 - Google Patents
一种减轻骨及骨关节疾病疼痛的药物 Download PDFInfo
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Abstract
本发明涉及一种减轻骨及骨关节疾病疼痛的药物，该药物是一种由非放射性金属离子与有机膦酸配体或其药用盐形成的络合物，本发明药物能稳定地作用于病变部位，通过小剂量单次治疗能抑制和防止病变组织进一步发展，达到长久的镇痛和缓解骨关节损伤的效果，见效快，无副作用。
Description
本发明涉及一种减轻骨及骨关节疾病疼痛的药物
许多疾病如骨关节炎，风湿性关节炎，转移性骨癌等疾病都会影响和破坏骨骼和骨关节，并引起疼痛，疼痛感与骨组织受损的程度和疾病的轻重有关，随着病程的延长，疼痛和骨关节损伤会逐渐加剧。目前医学界对大部分骨疾病还没有找到完全解决的治疗方法，而是集中在止痛消炎和保留关节及肌肉的功能上。
治疗风湿性疾病和关节炎的首选方法是药物治疗，利用消炎药物抑制或消除滑膜发炎，起到改善关节功能的作用。临床上常使用阿司匹林和水杨酸盐等镇痛剂抑制发炎，暂时缓解疼痛。风湿性关节炎的治疗中常使用D-青霉胺(配尼西林的天然替代品)，但这类药物也只能减缓疾病的发展。大多数治疗药物都存在着作用时间慢的缺点，在确定药物对病人是否有效之前，通常需要2-6个月的服用期才能对它作出评定，而且这些药物对于一些病人还可能产生严重的副作用。药物进入人体后，皮肤、肝、泌尿系统和其它要害器官可能会受到影响，因此使用者要认真监视病情，限制药物副作用的扩大。由于多数药物只能暂时缓解病痛，使用中必须连续服用，随着病情的发展所需的用药剂量逐渐增高，因而副作用也逐渐变大。许多病人还接受其它的治疗，增加了副作用的危险性和药物之间的相互作用，从而使问题更复杂化。市场上一种用于解除转移性骨癌病人的疼痛的新方法是利用亲骨性配体将放射性核素输送到病灶部位，如使用β-放射性核素186Re或153Sm与膦酸的络合物对病人进行静脉注射能有效解除转移性骨癌病人的疼痛。临床研究表明用这种方法注入人体的放射性核素不会只结合于骨受损部位，它还会分布至人体其它部位，使正常组织受到明显的核辐射损伤。另外放射性核素的生产比较困难，且寿命短，费用贵，这些因素限制了这一类药物的使用。
本发明的目的是提供一种能减轻转移性骨癌、关节炎和骨代谢紊乱病人的疼痛的药物。该药物的给药量较小，通过单次给药能起到长期减轻病痛的效果。药物进入人体后能有选择地被骨及骨关节吸收，尤其是有损伤的骨组织区域，并能在骨组织长期滞留，防止或抑制病变组织的进一步发展。
本发明用于减轻骨及骨关节疾病疼痛的药物是非放射性金属离子和膦酸盐组成的络合物。
本发明所述减轻骨及骨关节疾病疼痛的药物是非放射性金属离子与膦酸盐形成的水溶性的络合物，所述膦酸盐是由膦酸和其药用盐组成。
本发明所述减轻骨及骨关节疾病疼痛的药物中的非放射性金属离子带有≥+2的电荷。
本发明所述减轻骨及骨关节疾病疼痛的药物中的非放射性金属离子是从镓、锡、铟、钐、铈等金属元素中选出，这些金属的元素符号分别为Ga、Sn、In、Sm、Ce。
本发明所述药物中的膦酸是从有机二元膦酸、三元膦酸、四元膦酸或其混合物中选出。
本发明药物所述二元膦酸是从羟乙二膦酸、亚甲基二膦酸或其混合物中选出。
本发明药物所述三元膦酸是从次氮基三亚甲基膦酸选出。
本发明药物所述四元膦酸是从乙二胺四亚甲基膦酸、四氮杂环十二烷四亚甲基膦酸或其混合物中选出。
本发明所述药物中的膦酸还包括二亚乙基三胺五亚甲基膦酸。
上述有机膦酸的英文名称及缩写分别为：亚甲基二膦酸：methylenediphosphonic acid，MDP羟乙二膦酸：hydroxyethylenediphosphonic acid，HEDP次氮基三亚甲基膦酸：nitrilotrimethylenephosphonic acid，NTMP乙二胺四亚甲基膦酸：ethylenediaminetetramethylenephosphonicacid，EDTMP四氮杂环十二烷四亚甲基膦酸：tetraazacyclododecanetetra-methylenephosphonic acid，DOTMP二亚乙基三胺五亚甲基膦酸：diethylenetriaminepenta-methlyenephosphonic acid，DTPMP。
本发明所述减轻骨及骨关节疾病疼痛的药物包括但不限于如下化合物：Sn(IV)-MDP、Sn(IV)-EDTMP、Ga(III)-HEDP、Ga(III)-EDTMP和Ga(III)-DOTMP等。
其中MDP、EDTMP、HEDP的分子式结构如下：
本发明减轻骨及骨关节疾病疼痛的药物具有下述特点：该药物的有效组成是一个由金属离子和有机膦酸盐形成的络合物，有机膦酸对骨表面羟基膦灰石具有极强的亲和力，尤其在骨再生过程中，骨组织对膦酸盐的吸收更高。有机膦酸盐不易被人体内的生化酶如焦磷酸酶分解，药物进入人体后将主要分布于骨骼组织，尤其是炎性关节、成骨活性或破骨活性过高的病灶部位。药物中金属离子与骨组织形成不溶性无机磷酸盐化合物，因此可在骨病灶区内持久而有效地起到治疗作用。
另外，由于膦酸盐的络合作用，金属离子直接被送到骨病灶区域，避免了在人体内循环与其它生物分子的结合。
在骨损坏组织处膦酸与金属离子脱离，膦酸对于异常的破骨细胞活性或成骨细胞活性产生抑制作用，而金属离子与骨表面晶体形成非常稳定的络合物，沉积在病变区，这一沉积干扰和阻碍了骨消溶以及异常的成骨细胞的活动，从而有效抑制骨组织的进一步破坏。小剂量单次给药的情况下，该药物能达到长久的镇痛和缓解骨损伤的效果，而不需要每日每周服用药物。这种方法见效快，无副作用。
现通过实验合成实例对本发明能够减轻骨及骨关节疾病疼痛的药物作进一步说明。
例1 Sn(IV)-MDP络合物的制备
在盛有5ml蒸馏水的瓶内将25mg的SnCl2·H2O(其中Sn为13.15mg)与97mg的Na2MDP混合成Sn(IV)-MDP络合物。加入NaOH使所得溶液的pH值调成9-10，将溶液加热到80-90℃，10分钟，冷却后加入1ml的30％的H2O2，在开水浴内再次加热试样5分钟，再加入HCl，使溶液的pH值调成7-8，使用生理盐水将溶液的容积调到10ml，络合物中金属与配体(Sn∶MDP)的摩尔比约为1∶4。
例2 Sn(IV)-EDTMP络合物制备
在制备Sn(IV)-EDTMP络合物时，将氯化亚锡SnCl2.H2O溶于1N的HCl溶液中，再加入3倍摩尔比例的EDTMP钠盐(与锡相比过量)，搅拌均匀，混合物中再加入NaOH，直到获得清澈的溶液，按1∶1摩尔比加入CaCl2.H2O(基于EDTMP)，一滴一滴地加入NaOH，直到白色沉淀物消失，制备时需加热至100℃10分钟，以保证络合。冷却后再加入2倍当量的30％的H2O2，在沸水浴中再加热5分钟，最后利用HCl将pH值调到约8.5。
Claims (10)
1、一种减轻骨及骨疾病疼痛的药物，其特征为所述药物是非放射性金属离子和膦酸的络合物。
2、根据权利要求1所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述非放射性金属离子可与所述膦酸盐形成水溶性的络合物，所述膦酸盐是由膦酸和其药用盐组成。
3、根据权利要求1或2所述的一种减轻骨关节疾病疼痛的药物，其特征为所述非放射性金属离子带有≥+2的电荷。
4、根据权利要求3所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述非放射性金属离子从镓、锡、铟、钐、铈中选出，这些金属的元素符号分别为Ga、Sn、In、Sm、Ce。
5、根据权利要求1或2所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述膦酸是从有机二元膦酸、三元膦酸、四元膦酸或其混合物中选出。
6、根据权利要求5所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为二元膦酸是从羟乙二膦酸、亚甲基二膦酸或其混合物中选出。
7、根据权利要求5所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述三元膦酸是从次氮基三亚甲基膦酸选出。
8、根据权利要求5所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述四元膦酸是从乙二胺四亚甲基膦酸、四氮杂环十二烷四亚甲基膦酸或其混合物中选出。
9、根据权利要求1或2所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述膦酸包括二亚乙基三胺五亚甲基膦酸。
10、根据权利要求1所述的一种减轻骨及骨关节疾病疼痛的药物，其特征为所述药物包括但不限于如下化合物：Sn(IV)-MDP、Sn(IV)-EDTMP、Sn(IV)-DOTMP、Ga(III)-EDTMP和Ga(III)-DOTMP。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98100080A CN1092962C (zh) | 1998-01-26 | 1998-01-26 | 一种减轻骨及骨关节疾病疼痛的药物 |
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| CN98100080A CN1092962C (zh) | 1998-01-26 | 1998-01-26 | 一种减轻骨及骨关节疾病疼痛的药物 |
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| Publication Number | Publication Date |
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| CN1187350A CN1187350A (zh) | 1998-07-15 |
| CN1092962C true CN1092962C (zh) | 2002-10-23 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1063615A (zh) * | 1990-06-18 | 1992-08-19 | 陶氏化学公司 | 放射性药物制剂，其给药方法及制备方法 |
| CN1112023A (zh) * | 1994-12-05 | 1995-11-22 | 中国核动力研究设计院成都同位素应用研究所 | 用于治疗类风湿性疾病的药物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1063615A (zh) * | 1990-06-18 | 1992-08-19 | 陶氏化学公司 | 放射性药物制剂，其给药方法及制备方法 |
| CN1112023A (zh) * | 1994-12-05 | 1995-11-22 | 中国核动力研究设计院成都同位素应用研究所 | 用于治疗类风湿性疾病的药物 |
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