CN104936592B - 一种注射用hpph冻干粉针制剂及其制备方法 - Google Patents
一种注射用hpph冻干粉针制剂及其制备方法 Download PDFInfo
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- PUUBADHCONCMPA-USOGPTGWSA-N 3-[(21S,22S)-11-ethyl-16-(1-hexoxyethyl)-4-hydroxy-12,17,21,26-tetramethyl-7,23,24,25-tetrazahexacyclo[18.2.1.15,8.110,13.115,18.02,6]hexacosa-1,4,6,8(26),9,11,13(25),14,16,18(24),19-undecaen-22-yl]propanoic acid Chemical compound CCCCCCOC(C)C1=C(C2=NC1=CC3=NC(=CC4=C(C5=C(CC(=C6[C@H]([C@@H](C(=C2)N6)C)CCC(=O)O)C5=N4)O)C)C(=C3C)CC)C PUUBADHCONCMPA-USOGPTGWSA-N 0.000 title claims abstract description 41
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Abstract
一种注射用HPPH冻干粉针制剂及其制备方法。该冻干粉针制剂含有HPPH、助溶剂、增溶剂、赋形剂、pH调节剂。所述的HPPH冻干粉针制剂疏松，复溶性好，水分低，稳定性好。
Description
技术领域
本发明属于医药领域，具体涉及一种注射用HPPH冻干粉针制剂及其制备方法。
背景技术
抗肿瘤光敏剂HPPH为第二代光敏剂，它是由美国Roswell Park肿瘤研究所研究人员从绿色植物中提取、纯化，半合成的一种二氢卟酚类化合物，其结构式如下：
HPPH具有很好的光动力活性，理想的作用光谱以及很好的靶向性，对肿瘤组织的穿透率高，临床用于肺癌、食管癌、头面颈癌、膀胱癌、胃癌等多种实体肿瘤的治疗；较第一代相比，其光毒性明显降低，基本不需要避光，用量小，使用方便，是一种极富市场潜力的PDT治疗癌症用光敏剂，该药物现已成为抗癌药物研究的一大热点。国外已进行临床二期研究阶段，在国内，目前PDT市场几乎处于空白状态，现有的抗肿瘤光敏剂属于第一代光敏剂，毒副作用大，治疗费用昂贵。HPPH作为新一代光敏剂，其本身特有的优势以及较低的价格，将会走在竞争产品的前面，占据有利地位。
HPPH虽然具有非常好的抗癌疗效，但其在水中溶解性较差，且在水溶液中稳定性不佳，据报道用于国外临床二期研究的水针剂因为活性成分的溶解性问题，制剂过程中需要过量投料，且在溶液配制过程中，活性成分的溶解时间需要近18个小时，所得制剂的保存条件为-20℃，有效期为一年，因此该水针剂不利于大生产，在应用上也受到极大制约，且给临床用药安全和有效性造成一定影响。
发明内容
本发明的目的在于克服现有HPPH水针剂配制过程中溶解性不好，不能定量投料以及制剂稳定性较差的缺点，提供一种稳定的注射用HPPH冻干粉针制剂，该冻干粉针制剂可以定量投料、溶液配制时间短，制剂成品只需冷藏保存即可，甚至在常温下也能保存相当长一段时间，稳定性得到很大程度上的提高。
本发明公开了一种注射用HPPH冻干粉针制剂，其含有HPPH，助溶剂，增溶剂，赋形剂和pH调节剂，其中HPPH，助溶剂，增溶剂和赋形剂的重量百分含量为
在一个优选的实施方案中，所述HPPH，助溶剂，增溶剂和赋形剂的重量百分含量为
在一个优选的实施方案中，本发明提供的注射用HPPH冻干粉针制剂各原料的配比为：
在另一个优选的实施方案中，本发明提供的注射用HPPH冻干粉针制剂各原料的配比为：
其中，制剂配方中的溶剂为95％～100％(v/v)的乙醇。
其中，制剂配方中的助溶剂为碳酸钠；优选在制剂配制过程中，助溶剂以其在注射用水中的溶液形式使用。
其中，制剂配方中的增溶剂为聚氧乙烯蓖麻油(EL)、吐温类或聚乙二醇硬脂酸酯15，优选聚氧乙烯蓖麻油(EL)或聚乙二醇硬脂酸酯15。
其中，制剂配方中的赋形剂为甘露醇、乳糖或右旋糖酐，优选甘露醇。
其中，制剂配方中的pH调节剂为磷酸、盐酸或醋酸，优选磷酸；优选在制剂配制过程中，pH调节剂以其在注射用水中的溶液形式使用。
本发明还提供了一种注射用HPPH冻干粉针制剂的制备方法，其包括如下步骤：
a)将处方量的赋形剂移至装有适量注射用水的配料罐中，搅拌溶解，得溶液①；
b)将处方量的HPPH置于配料罐中，加入处方量的溶剂、助溶剂溶液和增溶剂，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至处方体积，滴加pH调节剂调节溶液的pH至6.0～8.0，优选6.5～7.5，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。
其中，步骤b)中配制溶液②时物料的加入顺序为：HPPH中依次加入处方量的溶剂、助溶剂溶液和增溶剂，实验证明按此加入顺序能达到较佳的溶解效果。
其中，步骤c)中冻干步骤包括：
1)预冻：将制品在-40～-50℃预冻2～4小时，使制品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温27～31小时；
3)解析干燥：将制品逐步升温至20℃，保温3～5小时。
本发明制备得到的注射用HPPH冻干粉针制剂组方合理，溶液配制耗时短，所得制剂疏松，复溶性好，水分低，具有较好的制剂稳定性，且暗毒性低，光敏性高。
具体实施方式
以下结合实施例对本发明进行详细说明，必须指出，以下实施例只用于说明本发明，而不是对本发明的限制。
实施例1
a)将处方量的甘露醇移至装有2000ml注射用水的配料罐中，搅拌溶解得溶液①；
b)称取处方量的HPPH置于配料罐中，加入处方量的无水乙醇，搅拌，加入处方量的碳酸钠溶液和聚氧乙烯蓖麻油，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至5000ml，接着滴加磷酸水溶液调节溶液pH至7.0，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。其中冻干程序如下：
1)预冻：将制品在-40～-50℃预冻3小时，使产品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温28小时；
3)解析干燥：将制品逐步升温至20℃，保温5小时。
实施例2
a)将处方量的右旋糖酐移至装有2500ml注射用水的配料罐中，搅拌溶解得溶液①；
b)称取处方量的HPPH置配料罐中，加入处方量的96％乙醇，搅拌，加入处方量的碳酸钠溶液和吐温80，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至5000ml，接着滴加磷酸水溶液调节溶液pH至6.5，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。其中冻干程序如下：
1)预冻：将制品在-40～-50℃预冻3.5小时，使产品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温29小时；
3)解析干燥：将制品逐步升温至20℃，保温4小时。
实施例3
a)将处方量的甘露醇移至装有3000ml注射用水的配料罐中，搅拌溶解得溶液①；
b)称取处方量的HPPH置于配料罐中，加入处方量的95％乙醇，搅拌，加入处方量的碳酸钠溶液和聚乙二醇硬脂酸酯15，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至5000ml，滴加磷酸水溶液调节溶液pH至7.8，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。其中冻干程序如下：
1)预冻：将制品在-40～-50℃预冻4小时，使制品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温31小时；
3)解析干燥：将制品逐步升温至20℃，保温3小时。
实施例4
a)将处方量的甘露醇移至装有4000ml注射用水的配料罐中，搅拌溶解得溶液①；
b)称取处方量的HPPH置于配料罐中，加入处方量的96％乙醇，搅拌，加入处方量的碳酸钠溶液和聚氧乙烯蓖麻油，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至5000ml，接着滴加磷酸水溶液调节溶液pH至7.3，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。其中冻干程序如下：
1)预冻：将制品在-40～-45℃预冻2.5小时，使产品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温29小时；
3)解析干燥：将制品逐步升温至20℃，保温4小时。
实施例5稳定性研究
将实施例1-4制备得到的冻干粉针与冻干前原液分别放置于40℃和5℃条件下，进行稳定性研究，测得的稳定性数据如下：
从上表的数据可知，冻干粉针制剂在5℃和40℃下，其杂质增长幅度和增长速率远远低于冻干前原液，因此其稳定性明显高于冻干前原液，从制剂的安全性、有效性综合考虑，选择冻干粉针作为优选的制剂处方。
实施例6稳定性研究
按实施例2、4的配方比例及工艺，另制备三个批次的冻干粉针制剂，将各批次分别放置于5℃条件下，进行稳定性研究，测得的稳定性数据如下：
从上表的数据可知，各批次冻干粉针制剂产品质量均一、批间重现性好，在5℃条件下，24个月内其杂质增长速度均非常缓慢，产品稳定性高。
Claims (13)
1.一种注射用HPPH冻干粉针制剂，其特征在于，其含有HPPH、助溶剂、增溶剂、赋形剂和pH调节剂，其中HPPH、助溶剂、增溶剂和赋形剂的重量百分含量为
其中所述的助溶剂为碳酸钠；
所述的增溶剂为聚氧乙烯蓖麻油、吐温类或聚乙二醇硬脂酸酯15；
所述的赋形剂为甘露醇、乳糖或右旋糖酐。
2.根据权利要求1所述的注射用HPPH冻干粉针制剂，其特征在于，所述HPPH、助溶剂、增溶剂和赋形剂的重量百分含量为
3.一种注射用HPPH冻干粉针制剂，其特征在于各原料的配比为：
其中所述的助溶剂为碳酸钠；
所述的增溶剂为聚氧乙烯蓖麻油、吐温类或聚乙二醇硬脂酸酯15；
所述的赋形剂为甘露醇、乳糖或右旋糖酐。
4.根据权利要求3所述的注射用HPPH冻干粉针制剂，其特征在于各原料的配比为：
5.根据权利要求3或4所述的注射用HPPH冻干粉针制剂，其特征在于：所述的溶剂为95％～100％(v/v)的乙醇。
6.根据权利要求1～4任一项所述的注射用HPPH冻干粉针制剂，其特征在于：所述的增溶剂为聚氧乙烯蓖麻油或聚乙二醇硬脂酸酯15。
7.根据权利要求1～4任一项所述的注射用HPPH冻干粉针制剂，其特征在于：所述的赋形剂为甘露醇。
8.根据权利要求1或2所述的注射用HPPH冻干粉针制剂，其特征在于：所述的pH调节剂为磷酸、盐酸或醋酸。
9.根据权利要求1或2所述的注射用HPPH冻干粉针制剂，其特征在于：所述的pH调节剂为磷酸。
10.一种制备如权利要求1～9任一项所述的注射用HPPH冻干粉针制剂的方法，包括如下步骤：
a)将处方量的赋形剂移至装有适量注射用水的配料罐中，搅拌溶解，得溶液①；
b)将处方量的HPPH置于配料罐中，加入处方量的溶剂、助溶剂溶液和增溶剂，搅拌溶解，得溶液②；
c)将溶液②加入到溶液①中，搅拌，加注射用水至处方体积，滴加pH调节剂调节溶液的pH值至6.0～8.0，过滤除菌至储液罐，分装，半压塞，冻干，压塞，包装。
11.根据权利要求10所述的制备方法，其特征在于，步骤b)中配制溶液②时物料的加入顺序为：HPPH中依次加入处方量的溶剂、助溶剂溶液和增溶剂。
12.根据权利要求10所述的制备方法，其特征在于，步骤c)中所述的冻干步骤包括：
1)预冻：将制品在-40～-50℃预冻2～4小时，使制品冻结至实；
2)一次干燥：制品预冻结束后，开启真空泵抽真空至20～30帕，将制品温度升至-5℃，保温27～31小时；
3)解析干燥：将制品逐步升温至20℃，保温3～5小时。
13.根据权利要求10所述的制备方法，其特征在于，步骤c)中，滴加pH调节剂调节溶液的pH值至6.5～7.5。
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