CN107375218A - 一种碳酸司维拉姆口服缓释干混悬剂 - Google Patents
一种碳酸司维拉姆口服缓释干混悬剂 Download PDFInfo
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Abstract
本发明涉及一种碳酸司维拉姆干混悬剂，含有助悬剂35～55％，填充剂15～25％，黏合剂5～10％，糊精2～5％，硬脂酸镁2～5％，蔗糖0.1～1％，二氧化钛0.1～1％，该干混悬剂可以改善碳酸司维拉姆在体内的作用时间，提高药物的顺应性。
Description
技术领域
本发明属于药物制剂领域，涉及一种碳酸司维拉姆组合物及其制备方法。
背景技术
终末期肾病患者普遍存在高磷血症，而且高磷血症可引起甲状旁腺功能亢进和骨营养不良。近来研究发现高磷血症尚可诱发软组织和血管钙化，是终末期肾病患者死亡率及心血管疾病发生增高的重要因素。因此，有效控制血清磷水平成为降低终末期肾病患者死亡率和心血管疾病发生率的重要举措。目前高磷血症的治疗主要包括饮食限磷、透析治疗、磷结合剂的应用及必要时甲状旁腺的切除。首先应该限制饮食中磷的摄入，但是过于严格的限制又会造成营养不良，对于透析患者则尤为明显。充分的透析治疗可以清除体内多余的磷，然而当前广泛推行的每周3次，每次4h的血液透析方式常常不足以清除体内多余的磷。有90％～5％的终末期肾病患者需要服用磷结合剂治疗高磷血症。
碳酸司维拉姆是由美国Genzyme公司原研的用于结合磷酸的非吸收性离子交换树脂，商品名为RenvelaTM，是一种交联的聚烯丙胺碳酸盐，化学名为聚(烯丙基胺基-共-N，N’-二烯丙基-1，3-二氨基-2-羟基丙烷)碳酸盐，其分子结构类似于网状树脂结构。结构式如下：
a，b为伯胺基团的数目a+b＝9
c为交联基团的数目c＝1
m为一个较大的数表示延伸的聚合物网络。
研究发现，碳酸司维拉姆具有高度亲水性，可以在胃肠道内水合膨胀成数倍于原体积的凝胶，生理pH下其携带的多个氨基可在小肠内质子化而带正电，通过离子交换和氢键与小肠内的磷酸根与胆汁酸结合，降低人体血液中磷酸盐水平。不仅如此，相比较盐酸司维拉姆，由于含有的氯离子很少，所以可以避免肾衰病人的酸毒血症倾向。碳酸司维拉姆治疗高磷血症有如下优点：(1)大大降低终末期肾病患者血清磷水平；(2)与含钙、含铝磷结合剂相比，碳酸司维拉姆不会引起高钙血症或铝中毒，从而可给予患者较高剂量的钙三醇以便更好地控制继发性甲状旁腺功能亢进；(3)可避免使用患者出现血液酸毒症倾向。
2007年10月19日，FDA批准碳酸司维拉姆片上市，2009年8月12日，批准碳酸司维拉姆口服干混悬剂上市。目前司维拉姆已在美、日、加、与欧洲等共计40多国上市并广泛的使用。碳酸司维拉姆是新颖的磷酸根结合剂，不含钙和铝是其突出的优点，可有效地使没有透析的慢性肾衰患者血清磷酸水平降低。它可作为钙盐的合理替代品，用于肾功能衰竭晚期患者高磷血症的治疗；也可利用其与骨化三醇结合的特点，控制患者体内的甲状旁腺素水平和代谢性骨病，而不会引起高钙血症或铝中毒。本品口服后不吸收，几乎100％以粪便排泄，因此不增加肾脏负担。经研究发现，碳酸司维拉姆不溶于水，但具有亲水性，遇水后体积显著膨胀并成凝胶状。目前市售碳酸司维拉姆的剂型为片剂和干混悬剂，这两种剂型各有优劣，片剂体积较小，方便携带，作为长期用药具有无可比拟的优点，但由于本品用药剂量较大(2.4～4.8g/天)，市售片剂规格为800mg或400mg，由于碳酸司维拉姆原料可压性较差，因此辅料比例较高造成片剂体积较大，对于吞咽困难的患者用药带来较大的麻烦；干混悬剂分散于水中后可以解决了吞咽困难的弊端。
CN104800165A提供了碳酸司维拉姆干混悬剂，该混悬剂颗粒分布均匀、稳定性好、在胃肠的分布面积大、吸收快、生物利用度高、药物起效快，药效优于碳酸司维拉姆预混剂，但该混悬剂为速效药物，对于长期服用的患者而言，顺应性差。
发明内容
本发明的目的是针对现有技术上的上述缺陷，提供一种碳酸司维拉姆缓释干混悬剂，改善碳酸司维拉姆在体内作用时间，提高药物的顺应性。
本发明的另一个目的是提供该组合物的制备方法。
本发明可通过如下技术方案实现：
一种碳酸司维拉姆口服干混悬剂，其特征在于：含有碳酸司维拉姆30～50％，助悬剂25～35％，填充剂15～25％，黏合剂5～10％，硬脂酸镁2～5％，蔗糖0.1～1％和二氧化钛0.1～1％。
其中，助悬剂为羟丙基甲基纤维素和羧甲基纤维素钠的组合，其比例为1:1-5:1。
其中，填充剂为微晶纤维素。
其中，黏合剂为阿拉伯胶。
优选的，该干混悬剂由碳酸司维拉姆40％，羟丙基甲基纤维素和羧甲基纤维素钠30％，微晶纤维素20％，阿拉伯胶5％，硬脂酸镁4％，蔗糖0.5％，二氧化钛0.5％制成，其中羟丙基甲基纤维素和羧甲基纤维素钠的比例为1:1。
此外，本申请还提供了一种碳酸司维拉姆口服缓释干混悬剂，包括如下步骤：将碳酸司维拉姆、助悬剂、填充剂、黏合剂及助流剂分别过80目筛，矫味剂及着色剂分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥后得到碳酸司维拉姆干混悬剂。
本发明的碳酸司维拉姆缓释干混悬剂在较长时间维持患者血磷浓度，同时减少了服用次数，提高了患者的顺应性。
附图说明
图1服用实施例1药物后高血磷大鼠的血磷含量变化图；
图2服用实施例2药物后高血磷大鼠的血磷含量变化图；
图3服用实施例3药物后高血磷大鼠的血磷含量变化图；
图4服用实施例4药物后高血磷大鼠的血磷含量变化图；
图5服用实施例5药物后高血磷大鼠的血磷含量变化图；
图6服用实施例6药物后高血磷大鼠的血磷含量变化图。
具体实施方式
实施例1
碳酸司维拉姆180g、羟丙基甲基纤维素210g、微晶纤维素150g、阿拉伯胶30g、硬脂酸镁24g、蔗糖3g和二氧化钛3g。
将碳酸司维拉姆、羟丙基甲基纤维素、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例2
碳酸司维拉姆300g、羟丙基甲基纤维素150g、微晶纤维素90g、阿拉伯胶42g、硬脂酸镁12g、蔗糖5g和二氧化钛5g。
将碳酸司维拉姆、羟丙基甲基纤维素、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例3
碳酸司维拉姆240g、羟丙基甲基纤维素180g、微晶纤维素120g、阿拉伯胶30g、硬脂酸镁27g、蔗糖1.5g和二氧化钛1.5g。
将碳酸司维拉姆、羟丙基甲基纤维素、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例4
碳酸司维拉姆240g、羟丙基甲基纤维素90g、羧甲基纤维素钠90g、微晶纤维素120g、阿拉伯胶30g、硬脂酸镁27g、蔗糖1.5g和二氧化钛1.5g。
将碳酸司维拉姆、羟丙基甲基纤维素、羧甲基纤维素钠、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例5
碳酸司维拉姆240g、羟丙基甲基纤维素30g、羧甲基纤维素钠150g、微晶纤维素120g、阿拉伯胶30g、硬脂酸镁27g、蔗糖1.5g和二氧化钛1.5g。
将碳酸司维拉姆、羟丙基甲基纤维素、羧甲基纤维素钠、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例6
碳酸司维拉姆240g、羟丙基甲基纤维素150g、羧甲基纤维素钠30g、微晶纤维素120g、阿拉伯胶30g、硬脂酸镁27g、蔗糖1.5g和二氧化钛1.5g。
将碳酸司维拉姆、羟丙基甲基纤维素、羧甲基纤维素钠、微晶纤维素、阿拉伯胶及硬脂酸镁分别过80目筛，蔗糖和二氧化钛分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥分装得到碳酸司维拉姆干混悬剂。
实施例7高血磷大鼠体内实验
选用21只高血磷大鼠，体重190-200g，每3只为一组，灌胃给药，分别给予实施例1-6的干混悬剂于第0，0.5，1，2，4，6，8，10，12，24h取静脉血1ml，测定血液中磷含量(mmol/L)。
结果显示，本发明的干混悬剂具有良好的缓释效果，能够实现24小时内高血磷大鼠血液内磷浓度维持在较为平稳的水平，药物的耐药性更好，且助悬剂选择羟丙基甲基纤维素、羧甲基纤维素钠的组合相对于单独的助悬剂而言，缓释效果更好。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。
Claims (6)
1.一种碳酸司维拉姆口服缓释干混悬剂，其特征在于：含有碳酸司维拉姆30～50％，助悬剂25～35％，填充剂15～25％，黏合剂5～10％，硬脂酸镁2～5％，蔗糖0.1～1％，二氧化钛0.1～1％。
2.根据权利要求1所述的干混悬剂，其特征在于，所述助悬剂为羟丙基甲基纤维素和羧甲基纤维素钠的组合，其比例为1:1-5:1。
3.根据权利要求1所述的干混悬剂，其特征在于，所述填充剂为微晶纤维素。
4.根据权利要求1所述的干混悬剂，其特征在于，所述黏合剂为阿拉伯胶。
5.根据权利要求1所述的干混悬剂，其特征在于，该干混悬剂由碳酸司维拉姆50％，助悬剂25％，填充剂15％，黏合剂7％，硬脂酸镁2％，蔗糖0.5％，二氧化钛0.5％制成。
6.一种权利要求1-3所述的干混悬剂的制备方法，其特征在于：将碳酸司维拉姆、助悬剂、填充剂、黏合剂及助流剂分别过80目筛，矫味剂及着色剂分别过60目筛；称取配方量的碳酸司维拉姆、助悬剂及填充剂，加水并混合均匀，制备软材；称取配方量的黏合剂、助流剂、矫味剂及着色剂一并加入到上述软材中制成碳酸司维拉姆湿颗粒，干燥后得到碳酸司维拉姆干混悬剂。。
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| CN104800165A (zh) * | 2015-04-22 | 2015-07-29 | 青岛正大海尔制药有限公司 | 一种碳酸司维拉姆干混悬剂及其制备方法 |
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