CN110711174A - 一种泊沙康唑注射液中间体溶液配制方法 - Google Patents
一种泊沙康唑注射液中间体溶液配制方法 Download PDFInfo
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Abstract
本发明提供一种能显著缩短泊沙康唑注射液中间体溶液配制时间的制备方法。该方法首先将药物与辅料混合,然后使用溶剂溶解。制备工艺简单,可操作性强,制备工艺温和,药物不发生降解等。该工艺在保证产品质量的前提下,显著缩短工艺时间,降低生产成本。
Description
技术领域
本发明涉及一种泊沙康唑注射液配制方法。
背景技术
泊沙康唑(posaconazole)伊曲康唑的衍生物,化学名称:4-[4-[4-[4-[[(3R,5R)-5-(2,4- 二氟苯基)-5-(1,2,4- 三唑-1- 基甲基) 氧杂戊环-3- 基] 甲氧基] 苯基] 哌嗪-1- 基] 苯基]-2-[(2S,3S)-2- 羟基戊-3- 基]-1,2,4- 三唑-3- 酮。是Schering-Plough 制药有限公司研发的第三代抗真菌药。2005 年12 月在德国首次上市。其作用机理与其他唑类抗菌药物相同,是通过与羊毛甾醇14α- 脱甲基酶(CYP51 或Erg11p) 活性部位的血红素辅助因子结合,抑制真菌麦角甾醇的生物合成,破坏细胞膜的形成和完整性而起到抗菌作用。泊沙康唑克服了第一代三唑类药物抗菌谱窄、生物利用度低及耐药性等问题,其抗真菌的作用无论是在体内和体外都已经被证实具有广谱的活性,对念珠菌、各种曲霉菌及其他常见的和非常见的致病真菌均有较大活性。
2006 年9 月15 日美国FDA 批准泊沙康唑(40mg/mL) 口服混悬液上市销售,是第一个被FDA 批准的用于预防由侵袭性曲霉菌引起病变的抗菌药物。2013年11月25日批准泊沙康唑(100mg)缓释片上市销售,适用于13 岁及以上患者。2014年3月13日年FDA 已批准泊沙康唑注射液 (18mg/mL)上市,这是泊沙康唑的一种静脉注射(IV) 的新剂型,适用于18岁及以上患者。
泊沙康唑安全性好,无明显的肝、肾毒性,耐受性好,可用于需长期治疗的患者。在预防免疫功能缺陷(粒细胞缺乏、移植后使用免疫抑制剂或HIV 感染)患者的深部真菌感染方面,疗效明显优于氟康唑或伊曲康唑。目前本品主要用于临床预防侵袭性曲霉属真菌感染,适用于因免疫系统严重受损的患者,免疫系统严重受损包括造血干细胞移植(HSCT) 接受者患有的移植物抗宿主病(GVHD) 或恶性血液病患者因化疗而导致长期的中性粒细胞减少。
泊沙康唑是一种弱碱性、水溶性差的药物,在中性和碱性水溶液中泊沙康唑具有小于1μg/ml 的溶解度。具有差生物利用度和可变吸收。酸性条件下溶解度略有增加,在pH= 1 时为0.8 mg/mL,但是任然不能满足计划的每日给药剂量。因此,目前对该药物研究主要致力于增加药物的溶解度,以期达到有效血药浓度。
中国专利CN201710169203.7公开了泊沙康唑注射液采用改性β- 环糊精作为增溶剂、依地酸二钠为螯合剂制备成供静脉输注的水溶性液体制剂。专利实施案及药品说明书指出泊沙康唑注射液每一小瓶(16.7ml)含有300mg 的泊沙康唑及磺丁基倍他环糊精钠6.68g,依地酸二钠0.003 g,盐酸和氢氧化钠调节pH 至2.6,和注射用水。笔者按照该专利提供制备方法重复配制泊沙康唑注射液中间体溶液样品时,发现由于泊沙康唑的严重疏水性,在使用酸化后的磺丁基倍他环糊精钠、依地酸二钠溶液溶解原料药时,原料药漂浮并聚集在溶液表面,随搅拌加剧聚合成球状,不利于药物分散溶解,中间体溶液配制工艺时间约为36-48h。较长的中间体溶液制备时间不仅增加无菌制剂的质量风险,同时带来较高的工艺成本。本发明采用将原辅料预处理,调整酸化步骤的工艺方案明显缩短注射液中间体溶液制备时间。本方案仅采用物理方法将原辅料预处理,调整盐酸溶液加入步骤,不引人新物料,因此不影响成品化合物物理及化学稳定性。
发明内容
本发明提供一种能显著缩短泊沙康唑注射液中间体溶液配制时间的制备工艺方法。泊沙康唑注射液中包合活性药物为泊沙康唑,辅料包含磺丁基倍他环糊精钠、依地酸二钠、盐酸、氢氧化钠、水。该工艺方法采用物理混合的方法将原辅料预处理,然后使用合适溶剂及酸化剂处理混合物,最后定容至合适浓度,调节最终溶液pH制备中间体溶液。该中间体溶液适用于泊沙康唑注射剂生产。
针对此问题,本发明提供一种能显著缩短泊沙康唑注射液中间体溶液配制时间的制备工艺方法,其特征在于通过制剂手段将活性成分与辅料混合,制备成原辅料混合物;然后使用溶剂将原辅料混合物分散,制备原辅料混悬液;使用酸化剂将酸化原辅料混悬液,搅拌使原辅料溶解,然后加入其它辅料或辅料溶液搅拌溶解,使用溶剂定容。必要时使用碱液或酸液调节终溶液pH至规定值。该方法有利于疏水性活性成分的分散溶解,缩短制备工艺时间。
本发明通过制剂手段制备的原辅料混合物,其特征在于将泊沙康唑与磺丁基倍他环糊精钠混合,混合物中可包含或不包含其他辅料。其处方中泊沙康唑的重量百分比为0.1-80%,磺丁基倍他环糊精钠的重量百分比为10-97%,依地酸二钠的重量百分比为0-10%。水的重量百分比为0-10%,盐酸溶液的重量百分比为0-10%。
本发明采用的混合制剂手段为药学上可接受粉碎、过筛、混合的一种、两种或两种以上手段的结合。
使用溶剂将原辅料混合物分散及溶解时,所用溶剂一般为注射用水,但不排除使用其他药学上可接受的溶剂,如纯化水、盐酸溶液、氢氧化钠溶液、辅料溶液或乙醇溶液等。盐酸溶液、氢氧化钠溶液、辅料溶液是指按照溶液配制方法所能得到的所有浓度的溶液。
酸化剂一般选用盐酸溶液,但不排除使用柠檬酸、硫酸、马来酸、磷酸、乙酸、L- 酒石酸、D- 酒石酸、DL- 酒石酸、甲磺酸、萘磺酸、对甲苯磺酸、乳酸、L- 乳酸、L- 抗坏血酸和苹果酸、以及甘氨酸盐酸盐等作为酸化剂。
具体实施方式:
为更好地说明本发明,下面将结合具体实施例对本发明做进一步阐述,但本发明的保护内容并非限定于实施例。
实施例1 :
成分 | 重量/g |
泊沙康唑 | 0.3 |
磺丁基倍他环糊精钠 | 6.68 |
1mol/l盐酸溶液 | 0.5ml |
水 | 3ml |
0.0015mg/ml依地酸二钠水溶液 | 2ml |
制备方法:
(1)将泊沙康唑与磺丁基倍他环糊精钠置混合机中混合均匀,制备原辅料混合物;
(2)将原辅料混合物分散至水中,得原辅料混悬液;
(3) 向(2)中混悬液加入1mol/l盐酸溶液酸化。
(4)向(3)中所得酸化溶液中加入2ml依地酸二钠水溶液,持续搅拌体系至原辅料完全溶解。
(5) 将(4)步所得溶液用水定容至16.7ml,使用1mol/l氢氧化钠溶液调节pH至2.6。搅拌均匀即得泊沙康唑注射液中间体溶液。
实施例2 :
成分 | 重量/g |
泊沙康唑 | 0.3 |
磺丁基倍他环糊精钠 | 6.68 |
依地酸二钠 | 0.003 |
1mol/l盐酸溶液 | 3ml |
水 | 4ml |
制备方法:
(1)将泊沙康唑、磺丁基倍他环糊精钠与依地酸二钠置混合机中混合均匀,制备原辅料混合物;
(2)将原辅料混合物分散至2ml水中,得原辅料混悬液;
(3) 向(2)中混悬液加入1mol/l盐酸溶液酸化。
(4) 向(3)中所得酸化溶液中加入2ml水持续搅拌体系至原辅料完全溶解。
(5) 将(4)步所得溶液用水定容至16.7ml,使用1mol/l氢氧化钠溶液调节pH至2.6。搅拌均匀即得泊沙康唑注射液中间体溶液。
实施例3 :
成分 | 重量/g |
泊沙康唑 | 0.3 |
磺丁基倍他环糊精钠 | 0.3 |
依地酸二钠 | 0.003 |
1mol/l盐酸溶液 | 1ml |
水 | 2ml |
制备方法:
(1) 将泊沙康唑、磺丁基倍他环糊精钠与依地酸二钠置混合机中混合均匀,制备原辅料混合物;
(2) 将原辅料混合物分散至1ml水中,得原辅料混悬液;
(3) 向(2)中混悬液加入1mol/l盐酸溶液酸化。
(4) 向(3)中所得酸化溶液中加入1ml水持续搅拌体系至原辅料完全溶解。
(5) 将(4)步所得溶液用水定容至16.7ml,使用1mol/l氢氧化钠溶液调节pH至2.6。搅拌均匀即得泊沙康唑注射液中间体溶液。
实施例4 :
成分 | 重量/g |
泊沙康唑 | 0.3 |
磺丁基倍他环糊精钠 | 3.34 |
依地酸二钠 | 0.003 |
盐酸 | 0.1ml |
水 | 4ml |
制备方法:
(1) 将泊沙康唑、磺丁基倍他环糊精钠、依地酸二钠与盐酸置研钵中研磨混合均匀,制备原辅料混合物;
(2) 将原辅料混合物分散至4ml水中,得原辅料混悬液;
(3) 持续搅拌(2)步所得体系至原辅料完全溶解。
(4) 将(3)步所得溶液用水定容至16.7ml,使用1mol/l氢氧化钠溶液调节pH至2.6。搅拌均匀即得泊沙康唑注射液中间体溶液。
中间体溶液含量及有关物质检测
按中国药典2015年版高效液相测定方法进行。对比不同工艺制备所得中间体溶液有关物质变化。有关物质对比实验结果见图1。
不同实施例制备中间体溶液形状及配制时间时间
名称 | 中间体溶液外观 | 配制时间/min |
实施例一 | 无色澄清透明 | 30 |
实施例二 | 无色澄清透明 | 30 |
实施例三 | 无色澄清透明 | 45 |
实施例四 | 无色澄清透明 | 30 |
实验结果显示:所选择的配制工艺能够生产出质量合格的中间体溶液,该中间体溶液可供注射液的制备使用。同时,将原辅料混合后能够增加疏水性活性成分与水浸润能力,使活性成分充分分散水中,有利于其溶解。因此,制备工艺能够显著缩短中间体溶液配制时间。
附图说明:
不同实施例有关物质对比图附图1。
Claims (5)
1.一种能显著缩短泊沙康唑注射液中间体溶液配制时间的制备工艺方法,其特征在于:通过制剂手段将活性成分与辅料混合,制备成原辅料混合物;然后使用溶剂将原辅料混合物分散,制备原辅料混悬液;使用酸化剂将酸化原辅料混悬液,搅拌使原辅料溶解,然后加入其它辅料或辅料溶液搅拌溶解,使用溶剂定容,必要时使用碱液或酸液调节终溶液pH至规定值,制备成泊沙康唑注射液中间体溶液,该中间体溶液适用于泊沙康唑注射液生产。
2.根据权利要求1所述,通过制剂手段制备的原辅料混合物,其特征在于将泊沙康唑与磺丁基倍他环糊精钠混合,混合物中可包含或不包含其他辅料,其处方中泊沙康唑的重量百分比为0.1-80%,磺丁基倍他环糊精钠的重量百分比为10-97%,依地酸二钠的重量百分比为0-10%,水的重量百分比为0-10%,盐酸溶液的重量百分比为0-10%。
3.根据权利要求1所述,采用的混合制剂手段为药学上可接受粉碎、过筛、研磨、混合等有利于将两种物质混合均匀的方法的一种、两种或两种以上的结合。
4.根据权利要求1所述,使用溶剂将原辅料混合物分散及溶解时,所用溶剂一般为注射用水,但不排除使用其他药学上可接受的溶剂,如纯化水、盐酸溶液、氢氧化钠溶液、辅料溶液或乙醇溶液等,盐酸溶液、氢氧化钠溶液、辅料溶液是指按照溶液配制方法所能得到的所有浓度的溶液。
5.根据权利要求1所述,酸化剂一般选用盐酸溶液,但不排除使用柠檬酸、硫酸、马来酸、磷酸、乙酸、L- 酒石酸、D- 酒石酸、DL- 酒石酸、甲磺酸、萘磺酸、对甲苯磺酸、乳酸、L-乳酸、L- 抗坏血酸和苹果酸、以及甘氨酸盐酸盐等作为酸化剂。
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