CN111789828A - 一种硫酸依替米星脂质体吸入剂及其制备方法 - Google Patents
一种硫酸依替米星脂质体吸入剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种硫酸依替米星脂质体吸入剂及其制备方法,所述脂质体吸入剂由硫酸依替米星、磷脂、缓冲液、辅料适量制成。其重量份数为硫酸依替米星1份;磷脂15‑20份;缓冲液125‑150份,所述吸入剂的pH值为6.2‑6.4。制备方法为:取硫酸依替米星、磷脂和有机溶剂混合,溶解,浓缩去除有机溶剂,加入缓冲液,轻微振摇后经高压匀质切割,制得硫酸依替米星脂质体。加入辅料适量,溶解,过滤、灌装即可。该吸入剂具有优异的靶向作用,与普通的注射剂相比,生物利用度更高,且能够减少药物在毒性部位的浓集,大幅度提升药物的安全性。制备方法简便易行,适用于工业生产。
Description
技术领域
本发明涉及感染治疗的药物制剂领域,具体涉及一种硫酸依替米星脂质体吸入剂及其制备方法
背景技术
硫酸依替米星属于氨基糖苷类抗生素,与大多数抑制微生物蛋白质合成的抗生素不同,氨基糖苷类抗生素可起到杀菌作用,对静止期细菌的杀灭作用强,为静止期抗菌药。同时还具有与β-内酰胺等抗生素协同作用、对许多致病菌存在抗生素后效应(PAE)等特点。但是由于其耳、肾毒性比较大,很大程度的限制了其临床使用。
氨基糖苷类药物是浓度依赖性抗生素,浓度越高,杀菌作用越强,但药物的毒性也与血药浓度正相关。这也成为此类药物应用于临床最大的障碍,因此制剂研究的关键在于改变药物在体内的分布,提高病变部位血药浓度而减少药物在毒性部位的浓集。
脂质体技术是指将药物包裹在类脂质双分子层中形成的微球型载体的技术。由于脂质体材料与细胞膜成分相近,因此具有良好的生物相容性和安全性。同时脂质体对机体的刺激性低,能够提高主药的稳定性,降低主药毒性,具有靶向和缓释的作用。
硫酸依替米星主要以注射方式给药,为了将药物递送指呼吸道和肺部,需要将其制备成雾化吸入剂,但常规吸入剂在使用时刺激性强,味道浓烈,常使治疗中断,本发明经过研究,发现采用脂质体包裹硫酸依替米星,并将其制备成吸入剂,具有减少抗生素给药剂量,能够在局部提高抗生素浓度的作用,硫酸依替米星以脂质体形式、通过吸入的方式直接递送至肺部,在肺部药物会被非结核分枝杆菌感染的肺巨噬细胞所吸收,延长了硫酸依替米星在肺部的释放时间。使得这些药物能够在靶向部位持续保持在有效浓度水平的同时,降低了氨基糖苷类药物的系统毒性。
发明内容
本发明的目的是提供一种硫酸依替米星脂质体吸入剂的制备方法,针对该氨基糖苷类药物,脂质体剂型能够减少给药剂量,降低药物在使用过程中的毒性,且药物以吸入的方式进入人体,使得药物在靶向部位保持有效浓度,遮掩了刺激性味道,提高了该药物的治疗效果。
本发明提供了一种硫酸依替米星脂质体吸入剂,包括如下重量份数的原料:硫酸依替米星1份、磷脂15-20份、缓冲液125-150份、辅料适量。
进一步地,所述磷脂为大豆卵磷脂。
进一步地,所述缓冲液包括磷酸盐、碳酸盐或醋酸盐中的一种或几种。
进一步地,所述辅料包括等渗调节剂、pH调节剂、抗氧剂。
进一步地,所述等渗调节剂包括无机盐类等渗剂。
进一步地,所述无机盐类等渗调节剂为氯化钠,每个制剂单位中氯化钠等渗剂的量按质量百分比计为0.5-0.9%。
进一步地,所述pH调节剂为氢氧化钠溶液,更优选10%的氢氧化钠溶液。
进一步地,所述抗氧剂包括亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐中的一种或几种,每个制剂单位中所含抗氧剂按质量百分比计为0.001-0.005%。
本发明还提供了一种制备上述任一所述硫酸依替米星脂质体吸入剂的制备方法,包括以下步骤:
将硫酸依替米星、磷脂混合,然后加入有机溶剂溶解,浓缩去除有机溶剂,加入缓冲液,轻微振摇后经高压匀质切割,制得硫酸依替米星脂质体。再加入辅料适量,溶解,调节pH值为6.2-6.4,过滤,灌装即可。
进一步地,加入有机溶剂溶解过程中,控制溶解温度为50-60℃。
进一步地,高压匀质切割过程中,将加入缓冲液之后的混合液以 1200-1500rpm的转速切割2-3min,制得乳液后,在100-150Mpa压力下匀质循环 4-5次。
其中,有机溶剂为无水乙醇。
本发明与现有硫酸依替米星制剂相比具有如下优点:
1、由于脂质体经吸入给药能够在肺部形成半固态的脂质的载体传递系统,与现有市场上的硫酸依替米星注射液和粉针剂相比,生物相容性较好,在给药部位滞留时间长。
2、本发明的制剂具有较好的靶向性,能够降低该类抗菌药物的耳、肾等系统毒性。
以下通过具体实验例来说明本发明制备过程的确定及所具有的有益效果。
实验例1:硫酸依替米星脂质体工艺及处方的确定
1.、仪器与试药
1.1、仪器
高效液相色谱仪、恒温加热磁力搅拌器、粒度分析仪、Zeta电位分析仪、旋转蒸发仪、均质机
1.2、试药
依替米星对照品、三氟乙酸、甲醇、萘替米星对照品、硫酸依替米星脂质体、纯化水
2.硫酸依替米星脂质体包封率的测定
2.1色谱条件和系统适用性实验
用十八烷基硅烷键合硅胶为填充剂(pH范围0.8~8.0)(4.6mm×300mm, 5μm色谱柱);以0.2mol/L三氟醋酸溶液-甲醇(84:16)为流动相;流速为每分钟0.5ml;用蒸发光散射检测器检测(参考条件:漂移管温度为100℃,载气流速为每分钟2.6L)。取依替米星与奈替米星各适量,加水溶解并稀释制成每1ml 中各约含0.2mg的混合溶液,取20μl注入液相色谱仪,记录色谱图,见附图1。依替米星(出峰时间21min)与奈替米星(出峰时间25min)峰间的分离度(4.22) 符合要求(>4)。
2.2含量测定:取依替米星对照品适量,精密称定,加水溶解并分别定量稀释制成每1ml中约含1.0mg、0.5mg和0.25mg的溶液,作为对照溶液(1)、(2)、 (3)。精密量取对照溶液(1)、(2)、(3)各20μl,分别注入液相色谱仪。以对照品溶液浓度的对数值与相应峰面积的对数值计算线性回归方程,相关系数 (r)应不小于0.99;精密量取硫酸依替米星脂质体适量,加50%甲醇,振摇,使脂质体溶解至溶液澄清,定容。取20μl注入色谱仪,记录峰面积,计算硫酸依替米星脂质体中依替米星含量。
2.3包封率的测定:取硫酸依替米星5.0ml置于超滤杯中,密封后用氮气加压,收集续滤液。经HPLC法测定续滤液中的药物含量(mf),精密量取硫酸依替米星脂质体溶液1ml,用一定量50%甲醇破坏后进样,测定脂质体溶液中的药物含量为(mt),包封率的计算公式为:EE=(mt—mf)/mt×100
2.4处方的单因素考查
以脂质体包封率为主要考查指标,考查药脂比、缓冲液pH值、溶解温度的影响。
2.4.1药脂比
按照上述方法制备硫酸依替米星脂质体,改变硫酸依替米星与大豆卵磷脂的质量比,质量比分别为1:10、1:15、1:20、1:25、1:30;按上述包封率测定的方法测定脂质体的包封率,考查硫酸依替米星原料药与大豆卵磷脂的质量比对药物包封率的影响,结果见附图2。
2.4.2缓冲液pH值
按照上述方法制备硫酸依替米星脂质体,改变缓冲液的pH值,使缓冲液的 pH值分别为7.40、6.00、5.50、5.00、4.50,按照上述包封率测定的方法测定脂质体的包封率,考查pH值对药物包封率的影响,结果见附图3。
2.4.3溶解温度
类脂溶液的溶解温度分别设定为40、45、50、55、60℃,其他工艺条件按照上述方法进行硫酸依替米星脂质体,按照上述包封率测定的方法测定脂质体的包封率,考查有机溶剂的溶解温度对药物包封率的影响,结果见附图4。
2.4.4正交设计优化脂质体处方和工艺
在单因素考查的基础上,筛选出影响脂质体包封率的3个因素。以这3个因素作为主要考查因素,每个因素选取3个水平(见表1),采用正交设计法进行实验(见表2),以硫酸依替米星脂质体的包封率为评价指标,选出最优的脂质体制备处方和工艺。由结果可看出,该正交表中每一实验均能够达到包封率大于 85%,因此工艺合理且可重复实现。经分析可知最优处方为药脂比1:20、缓冲液 PH值为7.40、溶解温度50℃。
表1不同影响因素和水平设计正交表
表2正交实验设计结果
实验序号 | 药脂比 | 缓冲液pH | 溶解温度(℃) | EE% |
1 | 1:20 | 7.40 | 50 | 91.36 |
2 | 1:20 | 6.00 | 55 | 88.62 |
3 | 1:20 | 5.00 | 60 | 86.65 |
4 | 1:15 | 7.40 | 55 | 90.51 |
5 | 1:15 | 6.00 | 60 | 87.29 |
6 | 1:15 | 5.00 | 50 | 90.02 |
7 | 1:30 | 7.40 | 60 | 90.62 |
8 | 1:30 | 6.00 | 50 | 88.11 |
9 | 1:30 | 5.00 | 55 | 88.63 |
将上述实验分析所得最优处方制得脂质体进行粒径及电位测定,测定结果如下:
平均粒径为(172±25)nm,粒径分布在平均粒径的比例为95%。
Zeta电位:经电位分析仪测定脂质体表面的Zeta电位平均值为(-25.8±1.1) mV,说明表面荷负电。
实验例2硫酸依替米星脂质体吸入制剂辅料的确定是经过实验筛选的,筛选实验如下:
根据上述实验例1中的色谱条件和系统适用性实验进行有关物质的测定,将筛选实验中制得的各吸入剂放置在不同的条件下(影响因素考查),经过不同的时间,进行有关物质的测定。要求供试品溶液中单个杂质不得过依替米星标示量的3.0%,杂质总量不得过依替米星标示量的6.0%。由结果可知,经过筛选后的辅料处方及工艺均能符合要求,表明该制剂所选处方及工艺能够制备出符合要求的吸入剂。
表3不同吸入剂处方配伍
表4不同条件下有关物质含量(%)
结果表明,处方1效果最佳,即本发明实施例1
实验例3组织分布试验
实验方法:取SD雄性大鼠30只,随机分为5组,分别为对照组、空白组、低剂量样品组、中剂量样品组、高剂量样品组,每组6只,对照组通过静脉注射给予硫酸依替米星氯化钠注射液,剂量为2mg/kg;空白组给予0.9%NaCl溶液;样品组给药为实施例1的硫酸依替米星脂质体吸入剂,低剂量:1mg/kg、中剂量: 1.5mg/kg、高剂量为2mg/kg;吸入给药时间为30min。分别于给药后10min、1h、 2h麻醉处死大鼠,取肺组织(含器官),全血经肝素钠抗凝后,离心(10000rpm,5min),取血浆部分,用上述含量测定方法进行检测。结果见表5。
表5肺组织药物浓度实验结果
结果表明,硫酸依替米星氯化钠注射液静脉注射后在1h与2h时,肺组织中药物浓度均显著性低于脂质体吸入剂给药各剂量组(P<0.01),在10min时,静脉给药的肺组织中药物浓度显著低于脂质体吸入给药的中、高剂量组,但与低剂量组无统计学意义上的差异(P>0.05)。同等剂量条件下(2mg/kg),硫酸依替米星吸入给药在各时间点的肺组织浓度是静脉给药的2.22-10.85倍。
附图说明
图1依替米星与萘替米星的色谱图
图2不同药物与磷脂质量比的药物包封率
图3不同pH值对药物包封率的影响
图4溶解温度对药品包封率的影响
具体实施方式:
为使本发明的技术方案便于理解,以下结合具体实施例对本发明一种硫酸依替米星脂质体吸入剂及其制备方法作进一步的说明。
实施例1
将硫酸依替米星15g、大豆卵磷脂300g混合,然后加入无水乙醇500ml溶解,溶解温度为50℃,经过旋转蒸发仪浓缩去除乙醇,加入pH7.4的PBS缓冲液2000ml,轻微振摇后经高压匀质切割,转速为1200rpm,切割时间为2min,制得乳液后,在150Mpa的压力下均质循环4次,制得硫酸依替米星脂质体,再加入氯化钠16g,焦亚硫酸钠0.072g,溶解,用10%氢氧化钠溶液调节pH值为6.2,过滤,灌装即可。
实施例2
将硫酸依替米星15g、大豆卵磷脂225g混合,然后加入无水乙醇400ml溶解,溶解温度为55℃,经过旋转蒸发仪浓缩去除乙醇,加入pH7.4的PBS缓冲液1875ml,轻微振摇后经高压匀质切割,转速为1500rpm,切割时间为3min,制得乳液后,在100Mpa的压力下均质循环5次,制得硫酸依替米星脂质体,再加入氯化钠10g,焦亚硫酸钠0.019g,溶解,用10%氢氧化钠溶液调节pH值为 6.4,过滤,灌装即可。
综上,所描述的实施例仅仅是为清楚表明该发明制剂所作的举例,并非对实施方式的限定,对于本领域内的技术人员来说,还可以做出其它不同形式的变化或变动,而由此引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种硫酸依替米星脂质体吸入制剂,其特征在于所述制剂由下列组分按重量份数制成:硫酸依替米星1份、大豆卵磷脂15-20份、缓冲液125-150份、辅料适量,其中,所述缓冲液包括磷酸盐、碳酸盐或醋酸盐中的一种或几种,其中所述辅料包括等渗调节剂、pH调节剂、抗氧剂。
2.如权利要求1所述的制剂,其特征在于,所述等渗调节剂为氯化钠溶液。每个制剂单位中所含等渗剂的量按质量百分比计为0.5-0.9%。
3.如权利要求1所述的制剂,其特征在于,所述pH调节剂为氢氧化钠溶液。
4.如权利要求1所述的制剂,其特征在于,所述抗氧剂包括亚硫酸盐、亚硫酸氢盐、焦亚硫酸盐中的一种或几种,每个制剂单位中所含抗氧剂按质量百分比计为0.001-0.005%。
5.如权利要求1所述的制剂,其特征在于,配方如下:硫酸依替米星1份,大豆卵磷脂15-20份,pH7.4的磷酸缓冲液125-150份,氯化钠,焦亚硫酸钠适量,氢氧化钠溶液调节pH值为6.2-6.4。
6.如权利要求1-5任一权利要求所述制剂的制备方法,其特征在于,包括以下步骤:
将硫酸依替米星、磷脂混合,然后加入有机溶剂溶解,浓缩去除有机溶剂,加入缓冲液,轻微振摇后经高压匀质切割,制得硫酸依替米星脂质体。再加入辅料适量,溶解,调节pH值为6.2-6.4,过滤,灌装即可,其中,有机溶剂为无水乙醇。
7.如权利要求6所述的制备方法,其特征在于,加入有机溶剂溶解过程中,控制溶解温度为50-60℃。
8.如权利要求6所述的制备方法,其特征在于,高压匀质切割过程中,将加入缓冲液之后的混合液以1200-1500rpm的转速切割2-3min,制得乳液后,在100-150Mpa压力下匀质循环4-5次。
9.如权利要求6所述的制备方法,其特征在于,步骤如下:将硫酸依替米星15g、大豆卵磷脂300g混合,然后加入无水乙醇500ml溶解,溶解温度为50℃,经过旋转蒸发仪浓缩去除乙醇,加入pH7.4的PBS缓冲液2000ml,轻微振摇后经高压匀质切割,转速为1200rpm,切割时间为2min,制得乳液后,在150Mpa的压力下均质循环4次,制得硫酸依替米星脂质体,再加入氯化钠16g,焦亚硫酸钠0.072g,溶解,用10%氢氧化钠溶液调节pH值为6.2,过滤,灌装即可。
10.如权利要求6所述的制备方法,其特征在于,步骤如下:将硫酸依替米星15g、大豆卵磷脂225g混合,然后加入无水乙醇400ml溶解,溶解温度为55℃,经过旋转蒸发仪浓缩去除乙醇,加入pH7.4的PBS缓冲液1875ml,轻微振摇后经高压匀质切割,转速为1500rpm,切割时间为3min,制得乳液后,在100Mpa的压力下均质循环5次,制得硫酸依替米星脂质体,再加入氯化钠10g,焦亚硫酸钠0.019g,溶解,用10%氢氧化钠溶液调节pH值为6.4,过滤,灌装即可。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111789827A (zh) * | 2019-04-01 | 2020-10-20 | 北京盈科瑞创新药物研究有限公司 | 一种硫酸依替米星雾化吸入用制剂及其制备方法 |
CN113209027A (zh) * | 2021-05-19 | 2021-08-06 | 无锡济煜山禾药业股份有限公司 | 一种治疗支气管扩张症的吸入微球制剂及其制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101579313A (zh) * | 2009-06-12 | 2009-11-18 | 王明 | 一种头孢氨苄脂质体及药物组合物 |
CN111228243A (zh) * | 2019-12-24 | 2020-06-05 | 珠海亿胜生物制药有限公司 | 一种雾化吸入用妥布霉素脂质体及其制备方法 |
-
2020
- 2020-07-15 CN CN202010677416.2A patent/CN111789828A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101579313A (zh) * | 2009-06-12 | 2009-11-18 | 王明 | 一种头孢氨苄脂质体及药物组合物 |
CN111228243A (zh) * | 2019-12-24 | 2020-06-05 | 珠海亿胜生物制药有限公司 | 一种雾化吸入用妥布霉素脂质体及其制备方法 |
Non-Patent Citations (2)
Title |
---|
谢秀琼等: "《现代中药制剂新技术》", 30 June 2004, 化学工业出版社 * |
陈小军等: "硫酸阿米卡星脂质体的制备及包封率测定", 《中国兽医科技》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111789827A (zh) * | 2019-04-01 | 2020-10-20 | 北京盈科瑞创新药物研究有限公司 | 一种硫酸依替米星雾化吸入用制剂及其制备方法 |
CN113209027A (zh) * | 2021-05-19 | 2021-08-06 | 无锡济煜山禾药业股份有限公司 | 一种治疗支气管扩张症的吸入微球制剂及其制备方法 |
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