CN114471747A - 多孔聚苯乙烯磺酸钠阳离子交换树脂及其制备方法和应用 - Google Patents
多孔聚苯乙烯磺酸钠阳离子交换树脂及其制备方法和应用 Download PDFInfo
- Publication number
- CN114471747A CN114471747A CN202210173888.3A CN202210173888A CN114471747A CN 114471747 A CN114471747 A CN 114471747A CN 202210173888 A CN202210173888 A CN 202210173888A CN 114471747 A CN114471747 A CN 114471747A
- Authority
- CN
- China
- Prior art keywords
- porous
- cation exchange
- exchange resin
- polystyrene sulfonate
- divinylbenzene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003729 cation exchange resin Substances 0.000 title claims abstract description 65
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Images
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
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Abstract
本发明提供了一种多孔聚苯乙烯磺酸钠阳离子交换树脂及其制备方法和应用,属于材料制备技术领域;本发明中,以苯乙烯为单体采用致孔剂进行悬浮聚合制备交联聚苯乙烯微球,并对其进行索氏提取、磺化等过程制备得到多孔聚苯乙烯磺酸钠阳离子交换树脂,满足药用辅料标准,并将其应用于盐酸维拉帕米制备脉冲缓释混悬剂。
Description
技术领域
本发明属于材料制备技术领域,具体涉及一种多孔聚苯乙烯磺酸钠阳离子交换树脂及其制备方法和应用。
背景技术
盐酸维拉帕米(Verapamil Hydrochloride,VH)作为苯烷基胺类选择性钙通道阻滞剂的一种,常被用来治疗原发性高血压,不仅具有调节血压的作用还可治疗心绞痛,抑制血管钙化,但其达峰时间较快,单剂口服盐酸维拉帕米片1~2h内达峰浓度,半衰期较短,需多次给药,方可维持治疗所需血药浓度,而单剂口服盐酸维拉帕米缓释片于5-7h内达峰浓度,可显著增加药物有效时间。高血压在老年人中的发病率极高,常用的片剂和胶囊剂等固体制剂对于老年群体服用十分不便,而口服液体缓控释混悬剂具有吸收快、可分剂量服用、易于包装运输等特点,尤其适合有吞咽困难患者服用。
离子交换树脂,如聚苯乙烯磺酸钠阳离子交换树脂(Amberlite IRP69),结构上其具有三维空间的网状骨架和以共价键结合不能移动的功能基团以及以离子键结合的可交换离子,离子交换树脂可与带同种电荷的药物通过离子键结合成药物树脂复合物,当药物树脂复合物进入人体后发生与载药相反的过程,与体液中的离子进行交换将药物释放出来发挥药物疗效,且树脂分子量较大仅有少量被人体吸收,具有提高药物稳定性、掩盖药物不良气味、加快药物溶出、对人体影响较小、可缓慢平稳释放药物等特点。
聚苯乙烯磺酸钠树脂对于药物的结合能力取决于药物的结构特性,例如其对盐酸可乐定、盐酸帕罗西汀等药物的载药量可达80%,而对盐酸维拉帕米的载药量仅有30%,药物利用率也非常低。这是因为聚苯乙烯磺酸钠与药物的结合机制为离子交换,载药量大小与其Na含量及K交换容量密切相关,而聚苯乙烯作为高交联聚合物分子,在二乙烯苯为交联剂的情况下聚合物微球结合十分紧密,造成后续磺化过程中磺化度偏低,导致碱交换过程中Na离子引入过少,因此与药物结合时交换容量低。
发明内容
针对现有技术中存在不足,本发明提供了一种多孔聚苯乙烯磺酸钠阳离子交换树脂及其制备方法和应用。本发明中,以苯乙烯为单体采用复合致孔剂进行悬浮聚合制备交联聚苯乙烯微球,并对其进行索氏提取、磺化等过程制备得到多孔聚苯乙烯磺酸钠阳离子交换树脂,满足药用辅料标准,并将其应用于盐酸维拉帕米制备脉冲缓释混悬剂。
本发明中提供了一种多孔聚苯乙烯磺酸钠阳离子交换树脂,所述多孔聚苯乙烯磺酸钠阳离子交换树脂以聚苯乙烯-二乙烯苯为树脂骨架;所述多孔聚苯乙烯磺酸钠阳离子交换树脂为规则球形,表面具有微孔,孔径为1~4nm。
本发明中还提供了上述多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,具体包括如下步骤:
(1)聚苯乙烯-二乙烯苯凝胶微球的制备:
油相:将去除阻聚剂的单体苯乙烯ST和去除阻聚剂的交联剂二乙烯苯DVB混合,然后加入引发剂过氧化苯甲酰BPO涡旋至其全部溶解,接着加入指示剂亚甲基蓝及致孔剂混合均匀后得到油相,充N2保护备用;
水相:将聚乙烯醇PVA溶于纯水中,充N2保护备用;
将油相加入至水相中搅拌均匀,然后通入N2,在回流反应装置中加热反应,反应结束后搅拌至温度降为室温,然后抽滤、洗涤、抽滤、烘干,得到聚苯乙烯-二乙烯苯PS-DVB凝胶微球;
(2)聚苯乙烯-二乙烯苯多孔微球的制备:
将PS-DVB凝胶微球进行索氏提取致孔剂,提取后水洗、烘干得到聚苯乙烯-二乙烯苯PS-DVB多孔微球;
(3)聚苯乙烯-二乙烯苯多孔微球的磺化:
将PS-DVB多孔微球置于氯仿中溶胀,机械搅拌状态下缓慢滴加磺化剂浓硫酸,然后升温反应,然后旋蒸除去反应中的氯仿,洗涤,抽滤,烘干,得到多孔苯乙烯-二乙烯苯磺化微球;
(4)多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
将多孔苯乙烯-二乙烯苯磺化微球加入NaOH中碱式交换,然后洗涤、抽滤、烘干得到多孔聚苯乙烯磺酸钠阳离子交换树脂。
步骤(1)中,苯乙烯、二乙烯苯、过氧化苯甲酰和致孔剂的用量比为13.06mL:4.25mL:0.1503g:18.017mL,亚甲基蓝在水相中的浓度为1~5ppm。
进一步的,步骤(1)中,苯乙烯、二乙烯苯、过氧化苯甲酰和致孔剂的用量比为13.06mL:4.25mL:0.1503g:18.017mL;所述亚甲基蓝在油相中的浓度为1~5ppm;所述0.6gPVA全部溶解后的浓度为6mg/mL。
进一步的,步骤(1)中,所述致孔剂为甲苯、正庚烷、环己醇、液体石蜡的任意一种或几种。
进一步的,步骤(1)中,油相和水相的体积比为1:4~7。
进一步的,步骤(1)中,加热反应的条件为在65-75℃保温反应2-3h,升温至75-85℃保温反应4-6h,最终升温至90-95℃保温反应2-3h。
进一步的,步骤(2)中,所述索氏提取的步骤为:以石油醚或丙酮为提取溶剂,PS-DVB凝胶微球:提取溶剂=1g:30-70mL的料液比回流提取12-48h,提取后水洗、烘干。
进一步的,步骤(3)中,PS-DVB多孔微球和磺化剂的固液比为1g:1~5mL。
进一步的,步骤(3)中,滴加磺化剂时温度控制在25℃,滴加结束后升温反应的条件为:先在55-65℃下反应3-6h,然后升温至65-75℃反应6-9h。
本发明中还提供了上述多孔聚苯乙烯磺酸钠阳离子交换树脂在制备药物树脂微囊混悬剂中的应用。
具体的,所述应用的步骤为:
(1)药物树脂复合物制备:
以制备得到的多孔聚苯乙烯磺酸钠阳离子交换树脂为载体,制备盐酸维拉帕米药物树脂复合物。
其中,所述多孔聚苯乙烯磺酸钠阳离子交换树脂与所述盐酸维拉帕米的质量比为1~5:1。优选的,所述树脂与所述盐酸维拉帕米的质量比为1~2:1。
(2)浸渍载药树脂制备:
为了防止载药树脂溶胀,采用浸渍剂提高药物树脂的稳定性,所述浸渍剂为25%的聚乙二醇。其中,所述浸渍剂与盐酸维拉帕米药物树脂复合物的质量比为1:0.3~1,得到浸渍的载药树脂复合物。
(3)药物树脂包衣微囊制备:
利用内外油相萃取原理溶剂采用乳化溶剂挥发干法进行包衣,包衣材料为尤特奇L100,由于包衣材料易容于甲醇、乙醇等极性较大溶剂,而乙醇沸点较高,难以挥发,故内油相采用甲醇-丙酮(1:5),外油相为液体石蜡,乳化剂为司盘80,分散剂为PEG400,于50℃进行包衣,后经石油醚洗、抽滤、55℃干燥即得盐酸维拉帕米药物树脂包衣微囊。
其中,包衣时的进风量为30-50m3·h-1;喷液速率为0.5-1.8mL·min-1;进风温度为40-50℃;当包衣微囊增重至30-60%后放出包衣树脂,经40-60℃干燥即得药物树脂微囊。
(4)药物树脂微囊混悬剂的制备:
取药物树脂复合物微囊一定量,加入适量混悬剂和纯化水混合均匀即得药物-树脂脉冲缓释混悬剂。
其中所述混悬剂为PVP、HPMC、西黄耆胶、海藻酸钠、阿拉伯胶、微晶纤维素、PEG、Carbopol、Avicel RC591等中的一种或几种。
另外可添加蔗糖、山梨糖醇或糖精钠、橘子香精、柠檬香精、香橙香精、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸中的任意一种或至少两种的组合改善混悬剂的风味。还可以添加适量抗氧化剂和防腐剂等,诸如焦亚硫酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯或苯甲酸钠中的任意一种或至少两种的组合提高药物稳定性。
进一步的,所述药物为盐酸维拉帕米。
与现有技术相比,本发明的有益效果在于:
通过对现有药用辅料聚苯乙烯磺酸钠进行结构改进,在悬浮聚合阶段加入致孔剂进行共聚,后将致孔剂提取后可产生大量微孔及介孔,大大提高后续磺化反应磺化度,提高磺酸基含量,提高药物树脂的可交换容量。采用本发明制备的树脂进行载药时,能够在提高载药量的同时减小药物树脂结合时的空间位阻影响,对比于现有市售树脂具有明显的优势。
附图说明
图1为聚苯乙烯-二乙烯苯多孔微球(a)和多孔聚苯乙烯磺酸钠阳离子交换树脂(b)的粒径分布图。
图2为低倍数下多孔聚苯乙烯磺酸钠阳离子交换树脂(a)、高倍数下多孔聚苯乙烯磺酸钠阳离子交换树脂(b)、低倍数下IRP69阳离子交换树脂(c)和高倍数下IRP69阳离子交换树脂(d)的扫描电镜图。
图3为聚苯乙烯-二乙烯苯多孔微球(a)和多孔聚苯乙烯磺酸钠阳离子交换树脂(b)的红外谱图。
图5为盐酸维拉帕米脉冲缓释混悬剂体外释放图。
具体实施方式
下面结合附图以及具体实施例对本发明作进一步的说明,但本发明的保护范围并不限于此。
实施例1:多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
(1)聚苯乙烯-二乙烯苯凝胶微球制备:
将0.6g聚乙烯醇(PVA)置于三颈烧瓶中,加入去离子水100mL,加热搅拌至PVA全部溶解,再将温度降至室温得水相,备用。
将13.06mL苯乙烯(ST)、4.25mL二乙烯苯(DVB)和0.1503g过氧化苯甲酰(BPO)混合物涡旋3分钟直至BPO全部溶解,向其中加入致孔剂甲苯-正庚烷混合物18.017mL(4:1),混合均匀得油相,备用。
将油相匀速加入水相中,搅拌均匀后,迅速将油浴温度升至70±0.5℃保温反应3h,继续升温至80±0.5℃,增加搅拌速度保温反应5h,后将温度升至95℃,增加搅拌速度保温反应2h。反应结束后,关闭加热并将三颈瓶移出油浴锅,继续保持搅拌状态,冷却至室温后抽滤,纯水200mL洗两次后使用250mL甲醇洗两次,滤过放入表面皿中于60℃烘箱中烘干5h,得聚苯乙烯-二乙烯苯凝胶微球(PS-DVB凝胶微球)。
(2)聚苯乙烯-二乙烯苯多孔微球制备:
称取5g的聚苯乙烯-二乙烯苯凝胶微球用18cm滤纸包裹后放入索氏提取器中,按1:24的料液比加入120mL丙酮,回流进行索氏提取,提取24h。提取结束后将滤纸包中的微球放置于60℃烘箱中烘干,即得聚苯乙烯-二乙烯苯多孔微球(PS-DVB多孔微球)。
(3)聚苯乙烯-二乙烯苯多孔微球磺化:
称取2g PS-DVB多孔微球按1:5的固液比加入氯仿溶胀0.5h,然后按1:2固液比缓慢滴加浓硫酸(边搅拌边滴加)进行磺化反应,滴加完毕后搅拌至均匀,升温至60℃,搅拌下保温反应3h,升温至65℃,保温反应9h,反应结束后停止加热和搅拌。待三颈烧瓶中溶液温度降至室温后将产物加入到盛有100mL纯水烧杯中,洗至中性后抽滤,加入丙酮清洗两次,每次两分钟充分震荡后过滤放入烘箱中,即得多孔苯乙烯-二乙烯苯磺化微球(多孔PS-DVB磺化微球)。
(4)多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
将多孔苯乙烯-二乙烯苯磺化微球放置于10%的NaOH溶液中搅拌2h进行Na交换制备多孔聚苯乙烯磺酸钠阳离子交换树脂,经水洗至中性,抽滤、烘干,得多孔聚苯乙烯磺酸钠阳离子交换树脂。
聚苯乙烯-二乙烯苯多孔微球和多孔聚苯乙烯磺酸钠阳离子交换树脂的粒度分布及扫描电镜见附图1、2。如图1和2所示,二者粒径分布均在微米级别,D90在160-190μm左右,粒径分布均匀并无团聚现象,PS-DVB多孔微球及自制树脂的粒径分布相似,从表中可以看出,磺化后PS-DVB多孔微球粒径稍有增加。扫描电境结果低倍数下可以看出多孔聚苯乙烯磺酸钠阳离子交换树脂球状明显,高倍数下可以看到表面具有许多孔洞。
本实施例中还参考美国、日本药典及天津药检所公示的药用辅料聚苯乙烯磺酸钠质量标准,对制备的多孔聚苯乙烯磺酸钠阳离子交换树脂和陶氏化学生产的IRP69进行如下项检测,包括性状、化学鉴别、氨鉴别、苯乙烯、水分、重金属、钠和钾交换量。检测结果见下表1,红外表征见附图3。
表1是多孔聚苯乙烯磺酸钠阳离子交换树脂与IRP69质量检测结果,从表1中可以看出,多孔聚苯乙烯磺酸钠阳离子交换树脂符合药典对聚苯乙烯磺酸钠药用辅料的所有要求,并且Na含量和K交换量对比于IRP69树脂更高。。
图3为聚苯乙烯-二乙烯苯多孔微球和多孔聚苯乙烯磺酸钠树脂的红外光谱图,从图中可以看出,苯环上不饱和C-H键的伸缩振动峰在3059、3024cm-1处;亚甲基上的C-H键的伸缩振动峰出现在2921、2848cm-1处;1601cm-1处为单取代苯环的骨架振动峰;1492、1450cm-1处对应的是亚甲基的弯曲振动峰;756、690cm-1处峰为苯环单取代的特征峰;900-756cm-1处的峰归属为苯环双取代的二乙烯苯上的C-H面外弯曲振动峰,表明二乙烯苯交联剂的成功引入,悬浮聚合反应制备PS-DVB成功。磺化后在1186cm-1和1126cm-1处出现两个强峰,分别为的磺酸基团S=O的反对称伸缩振动吸收峰和对称伸缩振动吸收峰,说明磺酸基成功引入,磺化反应成功。
实施例2:多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
(1)聚苯乙烯-二乙烯苯凝胶微球的制备:
将0.6g聚乙烯醇(PVA)置于三颈烧瓶中,加入去离子水100mL,加热搅拌至PVA全部溶解,再将温度降至室温得水相,备用。
将13.06mL苯乙烯(ST)、4.25mL二乙烯苯(DVB)和0.1503g过氧化苯甲酰(BPO)混合物涡旋3分钟直至BPO全部溶解,向其中加入致孔剂甲苯-正庚烷混合物18.017mL(4:1),混合均匀得油相,备用。
将油相匀速加入水相中,搅拌均匀后,迅速将油浴温度升至75±0.5℃保温反应3h,继续升温至85±0.5℃,增加搅拌速度保温反应6h,后将温度升至95℃,增加搅拌速度保温反应3h。反应结束后,关闭加热并将三颈瓶移出油浴锅,继续保持搅拌状态,冷却至室温后抽滤,纯水200mL洗两次后使用250mL甲醇洗两次,滤过放入表面皿中于60℃烘箱中烘干5h,得聚苯乙烯-二乙烯苯凝胶微球(PS-DVB凝胶微球)。
(2)聚苯乙烯-二乙烯苯多孔微球的制备:
称取2g的聚苯乙烯-二乙烯苯凝胶微球用18cm滤纸包裹后放入索氏提取器中,按1:50的料液比加入100ml丙酮,回流进行索氏提取,提取48h。提取结束后将滤纸包中的微球放置于60℃烘箱中烘干,即得聚苯乙烯-二乙烯苯多孔微球(PS-DVB多孔微球)。
(3)聚苯乙烯-二乙烯苯多孔微球的磺化:
称取2g PS-DVB多孔微球按1:5的固液比加入氯仿溶胀0.5h,然后按1:2固液比缓慢滴加浓硫酸(边搅拌边滴加)进行磺化反应,滴加完毕后搅拌至均匀,升温至60℃,搅拌下保温反应6h,升温至65℃,保温反应3h,反应结束后停止加热和搅拌。待三颈烧瓶中溶液温度降至室温后将产物加入到盛有100mL纯水烧杯中,洗至中性后抽滤,加入丙酮清洗两次,每次两分钟充分震荡后过滤放入烘箱中,即得多孔苯乙烯-二乙烯苯磺化微球(多孔PS-DVB磺化微球)。
(4)多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
将多孔苯乙烯-二乙烯苯磺化微球放置于10%的NaOH溶液中搅拌2h进行Na交换制备多孔聚苯乙烯磺酸钠阳离子交换树脂,经水洗至中性,抽滤、烘干,得多孔聚苯乙烯磺酸钠阳离子交换树脂。
实施例3:多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
(1)聚苯乙烯-二乙烯苯凝胶微球制备:
将0.6g聚乙烯醇(PVA)置于三颈烧瓶中,加入去离子水100mL,加热搅拌至PVA全部溶解,再将温度降至室温得水相,备用。
将13.06mL苯乙烯(ST)、4.25mL二乙烯苯(DVB)和0.1503g过氧化苯甲酰(BPO)混合物涡旋3分钟直至BPO全部溶解,向其中加入致孔剂甲苯-正庚烷混合物18.017mL,混合均匀得油相,备用。
将油相匀速加入水相中,搅拌均匀后,迅速将油浴温度升至70±0.5℃保温反应3h,继续升温至85±0.5℃,增加搅拌速度保温反应6h,后将温度升至90℃,增加搅拌速度保温反应2h。反应结束后,关闭加热并将三颈瓶移出油浴锅,继续保持搅拌状态,冷却至室温后抽滤,纯水200mL洗两次后使用250mL甲醇洗两次,滤过放入表面皿中于60℃烘箱中烘干5h,得聚苯乙烯-二乙烯苯凝胶微球(PS-DVB凝胶微球)。
(2)聚苯乙烯-二乙烯苯多孔微球的制备:
称取1.5g的聚苯乙烯-二乙烯苯凝胶微球用18cm滤纸包裹后放入索氏提取器中,按1:70的料液比加入105ml石油醚,回流进行索氏提取,提取12h。提取结束后将滤纸包中的微球放置于60℃烘箱中烘干,即得聚苯乙烯-二乙烯苯多孔微球(PS-DVB多孔微球)。
(3)聚苯乙烯-二乙烯苯多孔微球的磺化:
称取2g PS-DVB多孔微球按1:5的固液比加入氯仿溶胀0.5h,然后按1:2固液比缓慢滴加浓硫酸(边搅拌边滴加)进行磺化反应,滴加完毕后搅拌至均匀,升温至60℃,搅拌下保温反应6h,升温至65℃,保温反应3h,反应结束后停止加热和搅拌。待三颈烧瓶中溶液温度降至室温后将产物加入到盛有100mL纯水烧杯中,洗至中性后抽滤,加入丙酮清洗两次,每次两分钟充分震荡后过滤放入烘箱中,即得多孔苯乙烯-二乙烯苯磺化微球(多孔PS-DVB磺化微球)。
(4)多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
将多孔苯乙烯-二乙烯苯磺化微球放置于10%的NaOH溶液中搅拌2h进行Na交换制备多孔聚苯乙烯磺酸钠阳离子交换树脂,经水洗至中性,抽滤、烘干,得多孔聚苯乙烯磺酸钠阳离子交换树脂。
实施例4:盐酸维拉帕米脉冲缓释混悬液制备
本实施例中以盐酸维拉帕米脉为例,利用多孔聚苯乙烯磺酸钠阳离子交换树脂为载体,进行药物树脂复合物的制备。采用流化床包衣及缓释微囊化技术制备盐酸维拉帕米脉冲缓释微囊,进一步制备盐酸维拉帕米脉冲缓释混悬剂,并考察其体外释放行为。
(1)药物树脂复合物(VH-DRC)的制备:
以陶氏化学生产的IRP69聚苯乙烯磺酸钠阳离子交换树脂为对比,分别取250mg进口树脂和实施例1中制备的多孔聚苯乙烯磺酸钠阳离子交换树脂分别加入到50mL浓度为5mg·mL-1的VH溶液中,在37℃下进行载药60min,抽滤、烘干即得VH-DRC。
考察上述两种树脂制备的药物树脂复合物的载药量,采用公式分别计算二者的载药量,其中,C0(mg·mL-1)为VH的初始浓度;Ct(mg·mL-1)为t时刻VH的浓度;V(mL)为纯化水的体积;WF(mg)为加入离子交换树脂的质量;Qt(mg·mg-1)为t时刻的载药量。
考察结果如图4所示。图4为自制的多孔聚苯乙烯磺酸钠树脂及陶氏化学生产IRP69聚苯乙烯磺酸钠阳离子交换树脂的载药曲线示意图,从图中可以看出,陶氏化学生产IRP69聚苯乙烯磺酸钠阳离子交换树脂对盐酸维拉帕米的载药量低于30%,而自制多孔聚苯乙烯磺酸钠树脂的载药量可高达80%,大大提高盐酸维拉帕米的药物利用率。
(2)浸渍载药树脂的制备:
将30g PEG 4000加入100mL去离子水中制成25%(w/v)的水溶液,水浴加热至35℃待PEG 4000溶解后,降至室温加入15g的VH-DRC,搅拌35min,抽滤、烘干、过筛即得浸渍盐酸维拉帕米药物树脂复合物(浸渍VH-DRC)。
(3)药物树脂包衣微囊的制备:
利用内外油相萃取原理溶剂选用乳化溶剂挥发干法进行包衣,包衣材料为尤特奇L100,由于包衣材料易容于甲醇、乙醇等极性较大溶剂,而乙醇沸点较高,难以挥发,故内油相采用甲醇-丙酮(1:5),外油相为液体石蜡,乳化剂为司盘80,分散剂为PEG400,于50℃进行包衣,后经石油醚洗、抽滤、55℃干燥即得盐酸维拉帕米药物树脂包衣微囊。
(4)药物树脂微囊混悬剂的制备:
盐酸维拉帕米药物树脂微囊混悬剂的配方为:
盐酸维拉帕米包衣微囊:含药240mg;
Avicel CL 611:3g;
丙二醇:5g;
甘油:5g;
山梨糖醇(70%):40g;
糖精钠:0.05g;
橘子香精:0.009g;
FD&C黄6号:0.2g;
无水柠檬酸:0.15g;
尼铂金丙酯:0.06g;
柠檬酸钠二水合物:0.1g;
苯甲酸钠:12;
硅氧烷消泡剂:0.2g;
水:补至100mL。
药物树脂微囊混悬剂的制备:首先称取处方量的盐酸维拉帕米包衣微囊用润湿剂(甘油)润湿,另外将处方量的助悬剂(Avicel CL 611)、防腐剂(对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)矫味剂(山梨糖醇和糖精钠)、分散剂(丙二醇)、消泡剂(二甲基硅油乳液)搅拌溶解在双蒸水中、缓冲剂(柠檬酸和柠檬酸钠)加入已经配制好的润湿剂溶液中,并使其分散均匀,最后用双蒸水定容至100mL,则为配制好的盐酸维拉帕米脉冲缓释混悬液。
本实施例中还对上述制备得到的盐酸维拉帕米脉冲缓释混悬剂进行体外释放度实验,释放度测定参照2020版《中国药典》第四部释放度测定0931第二法-桨法,转速100r/min,温度37℃,为了减少包衣微囊损失本实验先以500mL 0.1mol/L HCl溶液为溶出介质,释放2h后加入0.235mol/L磷酸氢二钠400mL调节pH为6.8,保持转速不变,在规定取样时间点取样5mL,过0.45μm水膜后稀释,于278nm波长下测定吸光度并计算累积释药量。按照要求药物前2h在酸性阶段释放量应不超过10%。测定结果如图5所示。
图5为盐酸维拉帕米脉冲缓释混悬剂体外释放曲线,从图中可以看出药物前2h在酸性介质中释放量不超过10%,更换介质后,肠溶包衣膜破裂,药物迅速释放,8h释放量可达90%,脉冲缓释效果良好。
综上,本发明的多孔聚苯乙烯磺酸钠阳离子交换树脂可达到药用辅料级别,满足美国药典、欧洲药典、国家药检所相关文件要求,对于IRP69聚苯乙烯磺酸钠阳离子交换树脂其交换容量大大增加,将其应用于盐酸维拉帕米脉冲缓释混悬剂可以实现明显增加载药量及药物利用率的效果。
所述实施例为本发明的优选的实施方式,但本发明并不限于上述实施方式,在不背离本发明的实质内容的情况下,本领域技术人员能够做出的任何显而易见的改进、替换或变型均属于本发明的保护范围。
Claims (10)
1.一种多孔聚苯乙烯磺酸钠阳离子交换树脂,其特征在于,所述多孔聚苯乙烯磺酸钠阳离子交换树脂以聚苯乙烯-二乙烯苯为树脂骨架;所述多孔聚苯乙烯磺酸钠阳离子交换树脂为规则球形,表面具有微孔,孔径为1~4nm。
2.权利要求1所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,包括:
(1)聚苯乙烯-二乙烯苯凝胶微球的制备:
油相:将去除阻聚剂的单体苯乙烯ST和去除阻聚剂的交联剂二乙烯苯DVB混合,然后加入引发剂过氧化苯甲酰BPO涡旋至其全部溶解,接着加入指示剂亚甲基蓝及致孔剂混合均匀后得到油相,充N2保护备用;
水相:将聚乙烯醇PVA溶于纯水中,充N2保护备用;
将油相加入至水相中搅拌均匀,然后通入N2,在回流反应装置中加热反应,反应结束后搅拌至温度降为室温,然后抽滤、洗涤、抽滤、烘干,得到聚苯乙烯-二乙烯苯PS-DVB凝胶微球;
(2)聚苯乙烯-二乙烯苯多孔微球的制备:
将PS-DVB凝胶微球进行索氏提取致孔剂,提取后水洗、烘干得到聚苯乙烯-二乙烯苯PS-DVB多孔微球;
(3)聚苯乙烯-二乙烯苯多孔微球的磺化:
将PS-DVB多孔微球置于氯仿中溶胀,机械搅拌状态下缓慢滴加磺化剂浓硫酸,然后升温反应,然后旋蒸除去反应中的氯仿,洗涤,抽滤,烘干,得到多孔苯乙烯-二乙烯苯磺化微球;
(4)多孔聚苯乙烯磺酸钠阳离子交换树脂的制备:
将多孔苯乙烯-二乙烯苯磺化微球加入NaOH中碱式交换,然后洗涤、抽滤、烘干得到多孔聚苯乙烯磺酸钠阳离子交换树脂。
3.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(1)中,苯乙烯、二乙烯苯、过氧化苯甲酰和致孔剂的用量比为13.06mL:4.25mL:0.1503g:18.017mL;所述亚甲基蓝在油相中的浓度为1~5ppm;所述0.6gPVA全部溶解后的浓度为6mg/mL。
4.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(1)中,所述致孔剂为甲苯、正庚烷、环己醇、液体石蜡的任意一种或几种。
5.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(1)中,油相和水相的体积比为1:4~7。
6.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(1)中,加热反应的条件为在65-75℃保温反应2-3h,升温至75-85℃保温反应4-6h,最终升温至90-95℃保温反应2-3h。
7.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(2)中,所述索氏提取的步骤为:以石油醚或丙酮为提取溶剂,PS-DVB凝胶微球:提取溶剂=1g:30-70mL的料液比回流提取12-48h,提取后水洗、烘干。
8.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(3)中,PS-DVB多孔微球和磺化剂的固液比为1g:1~5mL。
9.根据权利要求2所述的多孔聚苯乙烯磺酸钠阳离子交换树脂的制备方法,其特征在于,步骤(3)中,滴加磺化剂时温度控制在25℃,滴加结束后升温反应的条件为:先在55-65℃下反应3-6h,然后升温至65-75℃反应6-9h。
10.权利要求1所述的多孔聚苯乙烯磺酸钠阳离子交换树脂在制备药物树脂微囊混悬剂中的应用。
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