CN104523590B - 一种丁酸氯维地平脂肪乳注射液 - Google Patents
一种丁酸氯维地平脂肪乳注射液 Download PDFInfo
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- CN104523590B CN104523590B CN201410744654.5A CN201410744654A CN104523590B CN 104523590 B CN104523590 B CN 104523590B CN 201410744654 A CN201410744654 A CN 201410744654A CN 104523590 B CN104523590 B CN 104523590B
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Abstract
一种丁酸氯维地平脂肪乳注射液,涉及丁酸氯维地平药物制剂领域,该注射液包括丁酸氯维地平以及金属螯合剂依地酸二钠。金属螯合剂依地酸二钠比例为0.0001至0.0009% w/v。本发明在保证药品质量的前提下大大降低了金属螯合剂依地酸二钠的用量,增加了药物的安全性与稳定性。
Description
发明领域
本发明涉及丁酸氯维地平药物制剂领域,具体而言是一种依地酸二钠含量低,安全性高、稳定性好的丁酸氯维地平脂肪乳注射液。
发明背景
丁酸氯维地平是一种二氢吡啶钙通道阻滞剂,适用于口服降压药不适用或无法获得满意疗效的高血压患者的治疗。丁酸氯维地平脂肪乳注射液(CleviprexTM)于2008年经FDA批准于美国上市。
丁酸氯维地平脂肪乳注射液属于注射乳剂,其制备过程中,在加热溶解时所使用的油相罐,初乳制备时所用的剪切机,以及均质时所用的高压均质机等,均为金属设备。由于制备过程中接触的金属设备较多,可能引入微量金属离子。微量的金属离子催化制剂中原辅料反应,产生杂质,影响药物质量,对人体产生危害。
FDA公布的丁酸氯维地平制剂(CleviprexTM)处方中依地酸二钠的用量为0.05mg/ml。
我们对静脉给药制剂中依地酸二钠使用情况进行了调研,检索到了两个FDA上市产品中使用辅料情况的数据库:(1)Inactive Ingredient Database;(2)InactiveIngredient for Currently Markted Drug Products。信息显示,静脉注射小针中依地酸二钠的参考用量为0.005-0.2%,静脉输注用产品(IV INFUSION)中依地酸二钠参考用量为0.00368-1.0%。
对FDA相关数据库检索结果显示,依地酸二钠在静脉给药制剂(含静脉输注用产品)作为金属螯合剂较为常用。但是,依地酸二钠可与钙离子结合成可溶的络合物引起钙的减少,静脉制剂中使用依地酸二钠会导致血钙下降。血钙下降可引起神经肌肉系统与心血管系统的相应症状。血钙的快速下降,可导致肌痉挛。严重的低钙血症能导致喉、腕足、支气管等痉挛,癫痫发作甚至呼吸暂停。还可出现精神症状如烦躁不安、抑郁及认知能力减退等。对心血管系统的影响,主要为传导阻滞等心律失常,严重时可出现心室纤颤等。心电图典型表现为QT间期和ST段明显延长。血钙的长时间快速下降可能出现低血钙危象,产生严重的随意肌及平滑肌痉挛,导致惊厥,癫痫发作,严重哮喘,症状严重时可引起喉肌痉挛致窒息,心功能不全,心脏骤停。现有的使用依地酸二钠作为金属螯合剂的静脉制剂中依地酸二钠含量较高,存在一定的安全隐患。
发明内容
本发明的目的是解决上述现有技术的不足,提供一种依地酸二钠含量低,安全性高、稳定性好的丁酸氯维地平脂肪乳注射液。
在不增加杂质个数以及杂质量的前提下,降低丁酸氯维地平脂肪乳注射液中金属螯合剂依地酸二钠的用量,从而得到安全性高、稳定性好的丁酸氯维地平脂肪乳注射液。
本发明的技术方案具体实施方法如下:
一种丁酸氯维地平脂肪乳注射液,其特征在于包含如下成分:丁酸氯维地平、油相、乳化剂、助乳化剂、渗透压调节剂、依地酸二钠和注射用水,各组分含量如下:
(1)丁酸氯维地平,为0.01~1.0% w/v;
(2)依地酸二钠,为0.0001~0.0009% w/v;
(3)油相,为5~30% w/v;
(4)乳化剂,为0.2~2.0% w/v;
(5)助乳化剂,为0.01~2% w/v;
(6)渗透压调节剂,为2~3% w/v;
(7)其余为注射用水。
本发明中加入适量的pH调节剂,使所制备的丁酸氯维地平脂肪乳注射液的pH 为6.0~8.0;
其中所述油相为:红花籽油,花生油,大豆油,中链甘油三酯,橄榄油,玉米油,葵花油,棉籽油,芝麻油,丙二醇二酯和单酸甘油酯中的至少一种。优选地,油相为:红花籽油,花生油,大豆油,中链甘油三酯,橄榄油,玉米油,葵花油,棉籽油,芝麻油;更优选地,油相为:大豆油,中链甘油三酯。
其中所述乳化剂为:蛋黄卵磷脂,大豆磷脂,合成的磷脂酰胆碱,纯化磷脂酰胆碱和氢化磷脂酰胆碱中的至少一种。优选地,乳化剂为,蛋黄卵磷脂,大豆磷脂中的至少一种;更优选地,乳化剂为蛋黄卵磷脂。
其中所述助乳化剂为:泊洛沙姆,泊洛沙胺,聚山梨醇酯,生育酚PEG琥珀酸酯,胆酸,脱氧胆酸,油酸,聚氧乙烯脱水山梨醇脂肪酸酯和脱水山梨醇脂肪酸酯中的至少一种。优选地,助乳化剂为:泊洛沙姆,聚山梨醇酯,油酸,聚氧乙烯脱水山梨醇脂肪酸酯,脱水山梨醇脂肪酸酯中的至少一种;更优选地,助乳化剂为油酸。
其中所述渗透压调节剂为:甘油,氯化钠,氯化钾,甘露醇中的至少一种。优选地,渗透压调节剂为:甘油,氯化钠中的至少一种;更优选地,渗透压调节剂为甘油。
其中所述pH调节剂为氢氧化钠,盐酸中的至少一种。优选地,pH调节剂为氢氧化钠。
本发明中加入了金属螯合剂依地酸二钠,依地酸二钠通过与金属离子的强结合作用,将金属离子包合到螯合剂内部,变成稳定的,分子量更大的化合物,从而阻止金属离子起作用。这样的制剂提高了药品的质量,降低药品不良反应,增加了患者的用药安全性。
附图说明
为了更清楚的说明本发明的具体实施方式,下面将对具体实施例中所需要使用的附图做简单介绍。
图1:FDA公布的原研处方依地酸二钠用量为0.005%w/v的丁酸氯维地平脂肪乳注射液有关物质色谱图。
图2为本发明中依地酸二钠用量为0.0009% w/v的丁酸氯维地平脂肪乳注射液有关物质色谱图。
图3为本发明中依地酸二钠用量为0.0005% w/v的丁酸氯维地平脂肪乳注射液有关物质色谱图。
图4为本发明中依地酸二钠用量为0.0001% w/v的丁酸氯维地平脂肪乳注射液有关物质色谱图。
图5为丁酸氯维地平的降解途径。
具体实施方式
一种丁酸氯维地平脂肪乳注射液,由丁酸氯维地平、油相、乳化剂、助乳化剂、渗透压调节剂、依地酸二钠、pH调节剂和注射用水组成,各组分含量为:有效成份的丁酸氯维地平:0.01~1.0%w/v;依地酸二钠:0.0001~0.0009%w/v;油相:5~30% w/v;乳化剂:0.2~2.0%w/v;助乳化剂:0.01~2%w/v;渗透压调节剂:2~3% w/v;pH调节剂适量;其余为注射用水。
其中所述油相为:红花籽油、花生油、大豆油、中链甘油三酯、橄榄油、玉米油、葵花油、棉籽油、芝麻油、丙二醇二酯和单酸甘油酯中的至少一种。优选地,油相为:红花籽油、花生油、大豆油、中链甘油三酯、橄榄油、玉米油、葵花油、棉籽油和芝麻油中的至少一种;更优选地,油相为:大豆油和中链甘油三酯中的一种或二者混合物。
其中所述乳化剂为:蛋黄卵磷脂,大豆磷脂,合成的磷脂酰胆碱,纯化磷脂酰胆碱和氢化磷脂酰胆碱中的至少一种。优选地,乳化剂为:蛋黄卵磷脂,大豆磷脂中的至少一种;更优选地,乳化剂为蛋黄卵磷脂。
其中所述助乳化剂为:泊洛沙姆,泊洛沙胺,聚山梨醇酯,生育酚PEG琥珀酸酯,胆酸,脱氧胆酸,油酸,聚氧乙烯脱水山梨醇脂肪酸酯,脱水山梨醇脂肪酸酯中的至少一种。优选地,助乳化剂为:泊洛沙姆,聚山梨醇酯,油酸,聚氧乙烯脱水山梨醇脂肪酸酯,脱水山梨醇脂肪酸酯中的至少一种;更优选地,助乳化剂为油酸。
其中所述渗透压调节剂为:甘油,氯化钠,氯化钾,甘露醇中的至少一种。优选地,渗透压调节剂为:甘油,氯化钠中的一种;更优选地,渗透压调节剂为甘油。
其中所述pH调节剂为氢氧化钠,盐酸中的至少一种。优选地,pH调节剂为氢氧化钠。
其中所述制剂的pH 为6.0~8.0。
实施例1
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.01% w/v;依地酸二钠:0.0001% w/v;葵花油:30% w/v;合成的磷脂酰胆碱:2.0% w/v;胆酸:2% w/v;甘露醇:2% w/v;氢氧化钠:适量;其余为注射用水。
实施例2
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.08% w/v;依地酸二钠:0.0003% w/v;花生油、橄榄油、葵花油和棉籽油任意比例的混合物:22% w/v;大豆磷脂、纯化磷脂酰胆碱和氢化磷脂酰胆碱任意比例的混合物:1.5% w/v;泊洛沙胺、生育酚PEG琥珀酸酯、胆酸和脱氧胆酸任意比例的混合物:1.8% w/v;氯化钠、氯化钾和甘露醇任意比例的混合物:2.2% w/v;氢氧化钠:适量;其余为注射用水。
实施例3
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.1% w/v;依地酸二钠:0.0005% w/v;中链甘油三酯和玉米油任意比例的混合物:18% w/v;蛋黄卵磷脂,大豆磷脂任意比例的混合物:1.2% w/v;泊洛沙姆、聚山梨醇酯、油酸任意比例的混合物:1.2% w/v;甘油和氯化钠任意比例的混合物:2.5% w/v;氢氧化钠:适量;其余为注射用水。
实施例4
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.3% w/v;依地酸二钠:0.0006% w/v;大豆油:15% w/v;蛋黄卵磷脂:1% w/v;聚氧乙烯脱水山梨醇脂肪酸酯:1% w/v;氯化钠:2.6% w/v;氢氧化钠:适量;其余为注射用水。
实施例5
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.5% w/v;依地酸二钠:0.0008% w/v;中链甘油三酯:10% w/v;大豆磷脂:0.7% w/v;油酸:0.8% w/v;甘油:2.8% w/v;氢氧化钠:适量;其余为注射用水。
实施例6
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:1.0% w/v;依地酸二钠: 0.0009% w/v;单硬脂酸甘油酯:5% w/v;纯化磷脂酰胆碱:0.2% w/v;泊洛沙姆:0.01% w/v;氯化钠:3% w/v;氢氧化钠:适量;其余为注射用水。
实施例7
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.65% w/v;依地酸二钠:0.00052% w/v;大豆油和中链甘油三酯混合物:16% w/v;蛋黄卵磷脂和大豆磷脂混合物:0.96% w/v;泊洛沙姆和油酸的混合物:1.1% w/v;甘油、氯化钠混合物:2.5% w/v;氢氧化钠:适量;其余为注射用水。
实施例8
一种丁酸氯维地平脂肪乳注射液,其组成为:有效成份丁酸氯维地平:0.58% w/v;依地酸二钠:0.00056% w/v;棉籽油:13% w/v;纯化磷脂酰胆碱:1% w/v;生育酚PEG琥珀酸酯:1% w/v;氯化钾:2.2% w/v;氢氧化钠:适量;其余为注射用水。
制备工艺
(1)整个过程在氮气保护下进行;
(2)按要求配比称取丁酸氯维地平、油相、乳化剂、助乳化剂,在55~85℃下混合搅拌溶解,混合均匀得油相混合物;
(3)按要求配比称取渗透压调节剂、依地酸二钠和注射用水,在40~70℃下搅拌溶解,得水相混合物;
(4)在40~70℃下,将水相混合物和油相混合物混合搅拌均匀,得初乳;
(5)用适量氢氧化钠调节初乳pH至7.0~9.0;
(6)将初乳经高压均质机均质,均质压力为500~1000bar,均质次数为5~10次,得中间体;
(7)将中间体灌装,灭菌,得丁酸氯维地平脂肪乳注射液。
按照以下处方及制备工艺分别制备含不同依地酸二钠的丁酸氯维地平脂肪乳注射液。
处方 | 处方1 | 处方2 | 处方3 | 处方4 |
依地酸二钠用量(% w/v) | 0.005 | 0.0009 | 0.0005 | 0.0001 |
丁酸氯维地平(g) | 0.5 | 0.5 | 0.5 | 0.5 |
大豆油(g) | 200 | 200 | 200 | 200 |
蛋黄卵磷脂(g) | 12 | 12 | 12 | 12 |
油酸(g) | 0.3 | 0.3 | 0.3 | 0.3 |
甘油(g) | 22.5 | 22.5 | 22.5 | 22.5 |
依地酸二钠(g) | 0.05 | 0.009 | 0.005 | 0.001 |
加注射用水至 | 1000ml | 1000ml | 1000ml | 1000ml |
处方1为FDA公布的丁酸氯维地平脂肪乳注射液处方,处方2、处方3和处方4为本发明所叙述依地酸二钠用量的处方。
将以上处方所制备的制剂,采用高效液相色谱法检测含量以及所含杂质。所得结果如下:
表1:不同处方量依地酸二钠对制剂有关物质的影响结果
由上表以及图1、2、3可以看出。当依地酸二钠用量在0.0001%~0.0009% w/v范围内,与FDA所公布的原研处方所制备的制剂中所含总杂质是基本一致的。本发明在保证产品质量的前提下,选用了一个远低于常用剂量的依地酸二钠用量范围,获得了安全性高的丁酸氯维地平脂肪乳注射液。
将处方3所示的丁酸氯维地平脂肪乳注射液进行血管刺激性试验、过敏性试验和体外溶血试验,结果表明本发明制备的丁酸氯维地平脂肪乳注射液是安全的。
其中处方1与处方3所得制剂的稳定性如表2,表3所示。
表2 处方1制剂的长期稳定性结果
表3 处方3制剂的长期稳定性结果
处方1为FDA公布处方所制备制剂,处方3为本发明中处方所制备制剂。长期稳定性结果显示,本发明所制备的制剂,在2~8℃长期储存时,pH值,粒径,含量以及有关物质等均无显著性变化,且与FDA公布处方所制备制剂的各项指标均无显著性差异。这表明,本发明所制备的丁酸氯维地平脂肪乳注射液稳定性良好。本发明中加入了微量的金属螯合剂依地酸二钠,依地酸二钠通过与金属离子的强结合作用,将金属离子包合到螯合剂内部,变成稳定的,分子量更大的化合物,从而阻止金属离子起作用。这样的制剂提高了药品的质量,降低药品不良反应,增加了患者的用药安全性。
Claims (8)
1.一种丁酸氯维地平脂肪乳注射液,其特征在于包含:丁酸氯维地平、油相、乳化剂、
助乳化剂、渗透压调节剂、依地酸二钠和注射用水,各组分含量如下:
(1)丁酸氯维地平,为 0.01~1.0% w/v ;
(2)依地酸二钠,为 0.0001~0.0009% w/v ;
(3)油相,为 5~30% w/v ;
(4)乳化剂,为 0.2~2.0% w/v ;
(5)助乳化剂,为 0.01~2% w/v ;
(6)渗透压调节剂,为 2~3% w/v ;
(7)其余为注射用水。
2.根据权利要求 1 所述的丁酸氯维地平脂肪乳注射液,其特征在于加入适量的 pH调节剂。
3.根据权利要求 2 所述的丁酸氯维地平脂肪乳注射液,其特征在于所述丁酸氯维地平脂肪乳注射液的 pH 为 6.0~8.0。
4.根据权利要求 1 或 2 或 3 所述的丁酸氯维地平脂肪乳注射液,其特征在于所述油相为:红花籽油,花生油,大豆油,中链甘油三酯,橄榄油,玉米油,葵花油,棉籽油,芝麻油中的至少一种。
5.根 据权利要求 1 或 2 或 3 所述的丁酸氯维地平脂肪乳注射液,其特征在于所述乳化剂为:蛋黄卵磷脂,大豆磷脂中的至少一种。
6.根据权利要求 1 或 2 或 3 所述的丁酸氯维地平脂肪乳注射液,其特征在于所述助乳化剂为:泊洛沙姆,聚山梨醇酯,油酸,脱水山梨醇脂肪酸酯中的至少一种。
7.根据权利要求 1 或 2 或 3 所述的丁酸氯维地平脂肪乳注射液,其特征在于其中所述渗透压调节剂为:甘油,氯化钠,氯化钾,甘露醇中的至少一种。
8.根据权利要求 2 或 3 所述的丁酸氯维地平脂肪乳注射液,其特征在于所述 pH 调节剂为氢氧化钠、盐酸中的至少一种。
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