CN115531300A - 河豚毒素注射型植入剂及其制备方法和用途 - Google Patents
河豚毒素注射型植入剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种河豚毒素注射型植入剂，其组分包括河豚毒素、载体材料、有机溶剂、溶剂添加剂和稳定剂。本发明还公开了该植入剂的制备方法及其用于长效缓释镇痛的用途。本发明的河豚毒素注射型植入剂，可在14天内缓慢释放河豚毒素，具有长效镇痛的效果，应用前景广阔。
Description
技术领域
本发明涉及医药技术领域，具体涉及河豚毒素的一种新剂型-生物降解性注射型在体植入剂。此外，本发明还涉及该植入剂的制备方法和用于镇痛的用途。
背景技术
疼痛是实际的或潜在的组织损伤所引起的一种预警机制，防止机体遭受压迫或进一步损伤，疼痛包括机体受到伤害性刺激后的痛感觉和所做出的痛反应，主要是癌症、类风湿性关节炎、手术、损伤以及骨髓等问题造成的。现有的镇痛药如吗啡、阿司匹林和芬太尼等药物使用时常伴有较多不良反应，且长期使用会使机体产生拮抗作用，但临床上使用镇痛药来缓解疼痛及预防休克又是必要的，由此，寻找一种新的安全有效的镇痛药一直是受人关注的重点。
河豚毒素(Tetrodotoxin，简称TTX)，分子式为C11H17O8N3，分子量为319.27g·mol-1，结构式如下，属于氨基全氢化喹唑啉类化合物，具有笼形结构，常温下，提取的河豚毒素为无色晶状固体，理化性质稳定，微溶于水，微溶于无水乙醇、乙醚；几乎不溶于其他有机溶剂，易溶于有机酸和无机酸水溶液。
河豚毒素是一种电压门控钠通道的阻滞剂，它能够选择性地结合到电压门控钠通道的外前庭上的α亚基，使得钠离子无法进入通道，从而产生抑制兴奋的作用。从结构上看则是河豚毒素的胍基与钠离子通道内的特异性受体蛋白上的羰基相互作用，使得进入通道的空间位置受阻，从而达到阻滞离子进入通道的作用，继而产生神经、肌肉的麻痹。河豚毒素与钠离子通道是1：1的结合，即一分子毒素结合一个钠通道，且其结合是可逆的，并且与K+、Mg2+、Ca2+等带正电荷的离子竞争受体。根据电压门控钠通道对河豚毒素的敏感性可分为TTX敏感型和TTX耐受型，两者分别介导激活电压较低失活较快的快钠电流和激活电压高失活较慢的慢钠电流。
基于其作用机制，河豚毒素已被研究应用于镇痛、局麻等应用研究方向，镇痛是目前河豚毒素在医药应用上研究最广最深的方向。作为典型的钠离子通道阻滞剂，河豚毒素能够通过减少Na+通道动作电位的传播和/或阻断与慢性疼痛相关的异位放电，从而达到镇痛作用。其优点是只需极低的剂量(3μg)即可达到镇痛作用，镇痛效果比吗啡强3000倍，且没有成瘾性，能够作为成瘾性镇痛药吗啡和杜冷丁的良好替代品，目前已报道的河豚毒素制剂包括口服制剂、喷雾剂、气雾剂、注射剂等多种剂型。然而，这些剂型通常需要频繁给药才能够维持镇痛效果，不仅使用不便，而且血药浓度波动较大，当血药浓度较高时，河豚毒素极易产生中毒现象，因此将河豚毒素制备成长效缓控释给药系统，能够更好地发挥其药用镇痛效果。
生物可降解注射型皮下植入剂是一种缓控释制剂，其特点是药物固体粉末和高分子聚合物溶液在临用时混合在一起再注射入皮下，注射入皮下后高分子聚合物溶液的溶剂迅速扩散到周围组织的体液中，使高分子聚合物基质在注射部位固化，通过水溶涨高分子聚合物的扩散释放和高分子聚合物表面或整体溶蚀释放达到缓释作用。该剂型制备工艺简单，条件温和，药物的活性损失小，载药量容易控制，药物包封完全，批量生产易于实现。使用生物可降解的高分子聚合物作为基质，具有良好的生物相容性，释药完毕后无需手术取出。该剂型很好地解决了植入剂和注射用微球在生产和应用过程中存在的问题，应用前景广阔。自2002年以来，美国FDA已连续批准Atrix Laboratory公司的醋酸亮丙瑞林注射用植入剂四个剂量规格产品(商品名为Eligard 7.5mg，Eligard 22.5mg，Eligard 30mg，Eligard 45mg)上市用于治疗晚期前列腺癌。但至今未见河豚毒素可生物降解注射型植入剂的相关报道。
发明内容
本发明要解决目前缺乏河豚毒素可生物降解注射型植入剂的技术问题，提供一种河豚毒素注射型植入剂，该植入剂能控制河豚毒素在体内长效稳定地释放，使河豚毒素在体内长期处于发挥镇痛作用的治疗窗口。
为了解决上述技术问题，本发明通过如下技术方案实现:
在本发明的一个方面，提供了一种河豚毒素注射型植入剂，该植入剂的组分包括河豚毒素、载体材料、有机溶剂、溶剂添加剂和稳定剂；所述载体材料为生物可降解的PLGA；所述有机溶剂为NMP或DMA；所述溶剂添加剂为醋酸甘油酯，其所占比例为有机溶剂总体积的0-60％；所述稳定剂为Mg(OH)2微粉。
优选的，所述载体材料为羧基封端的PLGA，其粘度为0.1-0.8dl/g。
在本发明的另一个方面，还提供了一种河豚毒素注射型植入剂的制备方法，包括如下步骤：
1)制备PLGA溶液：
按配比将一定量的PLGA粉末加入有机溶剂NMP或DMA混匀，加或不加醋酸甘油酯，涡旋振荡至PLGA完全溶解，得PLGA溶液；
2)制备河豚毒素注射型植入剂
临注射时，将河豚毒素药物和PLGA溶液按一定配比即时混合，加入少量Mg(OH)2微粉，制成均一混悬液，即为河豚毒素注射型植入剂。
步骤1)制备PLGA溶液时，各组分的配比为：
PLGA粉末 100～200mg
NMP或DMA 0.1～0.2ml
醋酸甘油酯 0～0.5ml。
步骤2)制备河豚毒素注射型植入剂时，各组分的配比为：
河豚毒素 1mg
PLGA溶液 0.1～0.3ml
Mg(OH)2微粉 0.5～2mg。
例如，取1mg河豚毒素微粉及1.0mg Mg(OH)2微粉加入到0.2ml PLGA溶液中，经均质乳化机匀化，得到含有河豚毒素的PLGA均一混悬液，将其吸入一次性注射器中，静置排出气泡，即可用于注入皮下。
在本发明的另一个方面，还提供了上述河豚毒素注射型植入剂在制备镇痛药物中的用途。
本发明的河豚毒素注射型植入剂，通过借助在体植入剂的缓控释体系来控制河豚毒素在体内长效稳定地释放，从而能够达到河豚毒素在体内长期处于发挥镇痛作用的治疗窗口，经体内外药物释放实验表明，本发明制剂的河豚毒素可缓释至14天，14天累积释放95％左右，缓释效果非常显著。因此，本发明的河豚毒素注射型植入剂，相较于已有的应用于镇痛领域的河豚毒素制剂，能够实现河豚毒素的长期镇痛作用，对长期遭受慢性疼痛及各类癌症患者带来更好的生活和治疗倾向，大大改善患者的生活质量，也是对河豚毒素临床使用的新探索。
附图说明
图1是本发明河豚毒素注射型植入剂的体外释放曲线图；
图2是本发明河豚毒素注射型植入剂的体内释放曲线图。
具体实施方式
下面结合附图和具体实施例，进一步阐述本发明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修改同样落入本发明权利要求所限定的范围。
下面结合附图及实施例对本发明进行详细描述。
仪器和材料：
PLGA(RG502H)，德国Boehringer Ingelheim公司；
PT3100高速均质乳化机，瑞士Polytron公司
NMP(药用级)，美国国际特品公司；
醋酸甘油酯(分析纯)，北京化学试剂公司；
Mg(OH)2微粉(化学纯)，上海试四赫维化工有限公司；
实施例1制备TTX注射型植入剂
将0.1g PLGA(RG 502H)加入到0.2ml NMP与醋酸甘油酯的混合溶剂(1:1，v/v)中，振摇使PLGA与有机溶剂充分接触，50℃水浴加热至PLGA完全溶解，冷却至室温，即为PLGA溶液。向溶液中加入河豚毒素1mg及研至100目以下的Mg(OH)2微粉1mg，用均质乳化机8000rpm匀化2min，即得均一的TTX粉末混悬液，亦即本发明TTX注射型植入剂。将其吸入一次性注射器中，静置排出气泡，即可用于注入皮下。
实施例2TTX注射型植入剂的体外释放实验
本实验分成6组，每组3份，分别将按实施例1制备的植入剂0.2ml注入到10ml具塞试管中，在试管中加入10ml等渗的磷酸盐缓冲液(pH 7.4)，1-7组依次在1、3、5、7、10、14天取出植入剂，冷冻干燥。冻干后的植入剂以2ml乙腈溶解，涡旋至无团块，15000rpm离心5min，去除上清液，沉淀再加入2ml乙腈洗涤，重复三次，将沉淀真空干燥，以10ml 2％的醋酸复溶，涡旋至全溶，15000rpm离心5min，取上清液进高效液相色谱仪，同上法，根据不同时间的植入剂中所残留的TTX浓度，计算出本发明植入剂的TTX累积释放百分率，实验平行三份，取平均值，制作释放曲线，结果见图1。
由图1可见，本发明TTX注射型植入剂的首日突释为18％左右，可缓释至14天，14天内累积释放达92％左右。
实施例3TTX注射型植入剂体内释放实验
取雄性SD大鼠(200-220g)18只，随机分为6组，每组3只，将实施例1制备的TTX注射型植入剂注入大鼠背部皮下，每鼠0.2ml，1-6组依次于注射后1、3、5、7、10、14天处死大鼠，取出植入剂，剥除植入剂表面的组织，冷冻干燥。冻干后的植入剂以2ml乙腈溶解，涡旋至无团块，15000rpm离心5min，去除上清液，沉淀再加入2ml乙腈洗涤，重复洗涤三次，将沉淀真空干燥，以10ml 2％的醋酸复溶，涡旋至全溶，15000rpm离心5min，取上清液进高效液相色谱仪检测TTX浓度。根据植入后不同时间的植入剂中所残留的TTX浓度，计算出本发明植入剂的TTX累积释放百分率，实验平行三份，取平均值，制作释放曲线，结果见图2。
由图2可见，本发明TTX注射型植入剂的首日突释为20％左右，可缓释至14天，14天内累积释放达95％左右。
对体内外累积释放百分率作线性回归，得线性回归相关系数为0.9189，说明本发明TTX注射型植入剂体内外释放相关性良好。
Claims (7)
1.一种河豚毒素注射型植入剂，其特征在于，该植入剂的组分包括河豚毒素、载体材料、有机溶剂、溶剂添加剂和稳定剂；所述载体材料为生物可降解的PLGA；所述有机溶剂为NMP或DMA；所述溶剂添加剂为醋酸甘油酯，其所占比例为有机溶剂总体积的0-60％；所述稳定剂为Mg(OH)2微粉。
2.根据权利要求1所述的河豚毒素注射型植入剂，其特征在于，所述载体材料为羧基封端的PLGA，其粘度为0.1-0.8dl/g。
3.一种河豚毒素注射型植入剂的制备方法，其特征在于，包括如下步骤：
1)制备PLGA溶液：
按配比将一定量的PLGA粉末加入有机溶剂NMP或DMA混匀，加或不加醋酸甘油酯，涡旋振荡至PLGA完全溶解，得PLGA溶液；
2)制备河豚毒素注射型植入剂
临注射时，将河豚毒素药物和PLGA溶液按一定配比即时混合，加入少量Mg(OH)2微粉，制成均一混悬液，即为河豚毒素注射型植入剂。
4.根据权利要求3所述的河豚毒素注射型植入剂的制备方法，其特征在于，步骤1)制备PLGA溶液时，各组分的配比为：
PLGA粉末 100～200mg
NMP或DMA 0.1～0.2ml
醋酸甘油酯 0～0.5ml。
5.根据权利要求3所述的河豚毒素注射型植入剂的制备方法，其特征在于，步骤2)制备河豚毒素注射型植入剂时，各组分的配比为：
河豚毒素 1mg
PLGA溶液 0.1～0.3ml
Mg(OH)2微粉 0.5～2mg。
6.权利要求1所述河豚毒素注射型植入剂在制备镇痛药物中的用途。
7.根据权利要求6所述的用途，其特征在于，所述镇痛药物为具有长效镇痛作用的缓释药物。
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| US20050232966A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Stabilized biodegradable neurotoxin implants |
| CN101039674A (zh) * | 2004-09-21 | 2007-09-19 | 埃斯蒂文博士实验室股份有限公司 | 河豚毒素及其衍生物用于治疗中枢神经源性神经痛 |
| CN101669905A (zh) * | 2009-09-08 | 2010-03-17 | 中国人民解放军第二军医大学 | 一种胸腺素α1注射型皮下植入剂 |
| CN103705910A (zh) * | 2013-12-31 | 2014-04-09 | 深圳翰宇药业股份有限公司 | 一种齐考诺肽注射型皮下植入剂及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050232966A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Stabilized biodegradable neurotoxin implants |
| CN101039674A (zh) * | 2004-09-21 | 2007-09-19 | 埃斯蒂文博士实验室股份有限公司 | 河豚毒素及其衍生物用于治疗中枢神经源性神经痛 |
| CN101669905A (zh) * | 2009-09-08 | 2010-03-17 | 中国人民解放军第二军医大学 | 一种胸腺素α1注射型皮下植入剂 |
| CN103705910A (zh) * | 2013-12-31 | 2014-04-09 | 深圳翰宇药业股份有限公司 | 一种齐考诺肽注射型皮下植入剂及其制备方法 |
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