CN1088777A - 用于癌病灶直接给药的化疗药物制剂的制备方法 - Google Patents
用于癌病灶直接给药的化疗药物制剂的制备方法 Download PDFInfo
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- CN1088777A CN1088777A CN 92114977 CN92114977A CN1088777A CN 1088777 A CN1088777 A CN 1088777A CN 92114977 CN92114977 CN 92114977 CN 92114977 A CN92114977 A CN 92114977A CN 1088777 A CN1088777 A CN 1088777A
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Abstract
本发明为用于癌病灶直接给药的化疗药物制剂
的制备方法，属于抗癌药物制剂工艺。本发明在不挑
出全身给药的脂质体的前提下，又针对细胞周期非特
异性抗癌药物，在给药时药物浓度提高一倍，疗效可
提高几倍至几十倍的特点，给出两类靶向性给药率趋
近于100％癌瘤实体直接注射给药的混悬型缓释注
射剂及注射用缓释脂质体的制备方法。
Description
本发明属于抗癌药物制剂工艺。
癌症是世界性公认的难治之症，世界各国政府认可使用的抗癌药物已有数十种之多。大多数都是口服、静注、腔内、肌注等全身给药疗法。此种化疗确实对癌瘤有抑制生长和杀灭作用。但在癌瘤受到抑制或部分受到杀灭的同时，人体正常组织（造血系统、解毒系统、泌尿生殖系统等）也相应的受到极大的摧残和伤害，最后导致人体正常组织抵抗不住药力的伤害而被迫中途停药。由于癌瘤组织没有被彻底杀灭，致使化疗后的一段时间内癌瘤复发、转移等成为必然。因此人们把希望寄托于靶向性较好的抗癌制剂脂质体的研究上。现有的脂质体的制备方法有薄膜法、逆向蒸发法、注入法、表面活性剂稀释法、挤压法等。但一般方法制出的脂质体（溶液）均存在包封率低、贮藏期短、易卸漏等问题，冷冻、喷雾干燥后所得的脂质体干品也存在着易粘连、吸湿、酸败变质及使用时用蒸馏水复溶后尚需挤压过滤匀化等难题。同时客观的说脂质体并不是只对癌瘤有较大的亲合力，在吞噬细胞丰富的组织如肝、脾、骨、髓肺等分布量也很高。因此说脂质体的靶向性也是相对而已。给药后的相应毒性也是难免的。
本发明的目的是在不排出该脂质体可用于全身给药的前题下，针对细胞周期非特异性抗癌药物，在给药时药物浓度提高一倍，疗效可提高几倍至其几十倍的特点，给出二类更适合于癌瘤实体直接给药靶向性给药率近100%的混悬型缓释注射剂及注射用缓释脂质体。
本发明的用于癌瘤灶直接给药的化疗药物制剂，主要包括混悬型缓释注射剂及三种脂质体制剂。其所选药物为那些具有细胞毒性在癌瘤实体内即可直接发挥作用的抗癌药物如：细胞周期非特异性药物有偏重于癌实体直接注射。烷化剂类：环磷酰胺、异环磷酰胺、苯丁酸氮芥、苯丙氨酸氮芥、盐酸氮芥、塞替派等;亚硝尿类;甲环亚硝尿卡氮芥、环己亚硝尿等;抗肿瘤抗生素类：更生霉素、阿霉素、表阿霉素、红比霉素、丝裂霉素等;杂类：米托蒽醌、甲苄肼、顺铂、卡铂、亚砷酸及其盐等。细胞周期特异性药物（偏重于全身给药用）有长春花生物碱、喜树碱、鬼白素、氟尿嘧啶、喃氟啶、氨甲喋吟、阿糖胞苷、愽来霉素、派来霉素、丙亚胺、6-疏基嘌呤等。
其中混悬型缓释注射剂的制备方法为：将药物非特异性药物溶剂（可选用植物油，苄甲酸苄酯、油酸乙酯等）助悬剂（可选用单、双三硬脂酸铝）分别予处理后，将助悬剂溶于溶剂中形成油凝胶，然后将药物与油胶充分混匀（或溶于油胶）再用胶体磨磨细至合格、灭菌分装即可。
其中三种脂质体制剂的制备方法：将药物（选用上述两大类药物中水溶液稳定的药物或水不溶性药物）依其荷电情况分为阳离子型、阴离子型两大类药物，并在水相中依其药物的归类加入相应的能使药物在水中溶解（成盐）的酸性缓冲剂（如柠檬酸、琥珀酸、醋酸或草酸等）或碱性缓冲剂（如碳酸钠、碳酸氢钠、磷酸钠、磷酸氢钠等）、油相（可选用豚脂、植物油、苄甲酸苄酯、油酸乙酯、氯仿等），油相助悬剂（可选用单、二、三硬脂酸铝等）脂质材料（可选用磷脂酰胆碱、卵磷脂酰胆碱、豆磷脂酰胆碱、氢化豆磷脂酰胆碱、二月桂酰卵磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二鲸蜡磷脂、二硬脂酰磷脂酰甘油、硫脂、胆固醇粪甾醇、胆甾烷、胆甾烷醇、α-生育酚等），高粘度聚合物的喷雾干燥抗凝剂，实体注射缓释剂（可选用海藻酸钠、甲基纤维素、羧甲基纤维素、聚乙烯比各烷酮、支链淀粉及胶类等）上述原、辅料经予处理后备用，将药物溶于内层水相缓冲液中，调PH4或9备用，将助悬剂及1/3量的磷脂、胆固醇分别溶于油相（油脂、氯仿混合液）中，然后将上述含药缓冲液在搅拌下加入油相中，进行乳化形成W/O型乳剂，再将此W/O乳用温和的方法除去大部分有机溶媒，形成浓缩的W/O乳剂，将此浓缩乳在搅拌的状态下加入含有总量2/3磷脂和胆固醇的液性调至PH6.5～7.5水溶液中，形成W/O/W型复合乳，①匀化后蒸发除去残留的有机溶媒，即得可用于全身给药的包封率高，卸漏率低的脂质体溶液;②若将此脂质体溶液与高粘度聚合物溶液充分混合均匀，即得可用于癌病灶直接给药的注射用缓释脂质体溶液;③若将上述匀化后的W/O/W型复合乳与高粘度聚合物溶液同时进行喷雾干燥，即得表面形成一层聚合物薄膜的防粘连、抗氧化的脂质体微粒。
本发明由于是在不排出可全身给药的基础上，立足于癌瘤实体直接给药，因此具有以下特点：①两种剂型给药均具有癌瘤实体得药剂量准确，可控，局部药物浓度高、疗效高、见效高、总体副作用小，②两种剂型均采取了增稠、缓释等手段，故定位性好、药物从病灶卸漏少、作用时间长，③由于本脂质体的内、中、外三层均采用了特殊的方式处理。因此本法制出的脂质体不仅适用于工业化大生产，而且解决了脂质体（溶液）保藏期短、易卸漏、包封率低、冷冻、喷雾干燥后所得干品存在的易粘连、吸湿、酸败及使用时用蒸馏水复溶后需用特定设备挤压过滤匀化等难题。
本发明的处方、工艺示例为：
例1：处方：环磷酰胺45g、单硬脂酸铝20g，中性花生油至1000ml。
工艺：将环磷酰胺气流粉碎至5μm以下备用取经由过滤，灭菌的中性花生油，与以油浸泡的单硬脂酸铝配成的8%油胶加温至120℃，保温1小时，再用上述中性花生油稀释成2%油凝胶混合均匀备用。将药物粉末与此油凝胶充分混合，再用胶体磨磨细至合格、灭菌、分装即可。
例2：处方及工艺为：将4g阿霉素加入60ml的PH为4的0.15M柠檬酸缓冲液中充分溶解后构成水相备用将30g含2%单硬脂酸铝的中性豆油凝胶、12g二硬脂酰卵磷脂酰胆碱及胆固醇（1∶09克分子比）分别溶于120g氯仿中构成油相。将上述水相加到油相中，用匀化器匀化，将W/O型乳剂，将此乳50℃以下减压状态下蒸发掉55～70%氯仿，得浓缩的W/O型乳剂，将此乳在搅拌的情况下加入含有24g二硬脂酰卵磷脂酰胆碱及胆固醇（1∶0.7克分子比）的经碳酸氢钠调PH7的600ml水溶液中，乳化成W/O/W型复合乳剂，然后将此复合乳与含6g甲基纤维素的600ml水溶液混合均匀后立即喷雾干燥，即可得表面形成一层甲基纤维素薄膜的脂质体微粒（约130克）分装即得。
注：使用时，脂质体微粒的复溶可利用甲基纤维素在冷水中易溶，在45℃以上温度的水中不溶的特性，可得均匀分散的脂质体悬浮液。
Claims (8)
1、用于癌瘤灶直接给药的化疗药物制剂的制备方法，其特征在于选用那些具有细胞毒性的在癌实体内即可直接发挥作用的抗癌药物(如：细胞周期非特异性药物(偏重于癌瘤实体直接注射用)有烷化剂类：环磷酰胺、异环磷酰胺、苯丁酸氮芥、苯丙氨酸氮芥盐酸氮芥、塞替派等；亚硝尿类；甲环亚硝尿、卡氮芥、环己亚硝尿等；抗肿瘤抗生素类：更生霉素、阿霉素、表阿霉素、红比霉素丝裂霉素等；杂类：米托蒽醌、甲苄肼、顺铂、卡铂、亚砷酸及其盐等。细胞周期特异性药物(偏重于全身给药用)有长春花生物碱类、喜树碱、鬼臼素类、喃氟啶、氟尿嘧啶、氨甲喋呤、阿糖胞苷博来霉素、派来霉素、丙亚胺、6-疏基嘌呤等)之中至少一种药物为原料与特定辅料相结合，加工成癌病灶直接给药的化疗药物的混悬型缓释注射剂及三种脂质体制剂。
2、如权利要求1所述的混悬型缓释注射剂，其特征在于溶剂可选用植物油，苄甲酸苄酯，油酸乙酯中至少一种，助悬剂选用单二、三硬脂酸铝中至少一种，助悬剂与溶剂的用量比为0.5∶100～5∶100，药物混悬颗粒度控制在5μm以下（或溶于油胶中）
3、如权利要求1所述的三种脂质体的制剂，其特征在于将药物依据其荷电情况溶于相应的缓冲液中（内层水相）调PH（使之成为水溶性盐），将豚脂（或油凝胶）及1/3量的磷脂、胆固醇溶液氯仿中构成油相，将上述水相加入到油相当中，进行乳化形成W/O型乳剂，将此乳剂用温和的方法除去大部分有机溶媒形成浓缩的乳，将此W/O浓缩乳在搅拌的状态下加入含有总量2/3磷脂和胆固醇的PH约等于7的水溶液中，乳化后形成W/O/W型复合乳，将此复合乳用不同的处理方法处理可得三种不同的脂质体：①将此复合乳，匀化后，蒸发除去残留的有机溶媒，即可得用于全身给药的包封率高、卸漏率低的脂质体溶液。②将①所得脂质体溶液与高粘度聚合物溶液充分混合均匀，即得可用于癌病灶直接药的注射用缓释脂质体溶液。③若将上述匀化后的W/O/W型复合乳与高粘度聚合物溶液同时进行喷雾干燥，即可得表面形成一层聚合物薄膜的防粘连、抗氧化的脂质体微粒。
4、如权利要求3所述的三种脂质体制剂的制备方法，其特征在于内水相中的缓冲剂应依其药物荷电的情况进行选择，当药物为阳离子型时，则需选用与其组成水溶性盐的酸性缓冲剂（如柠檬酸琥珀酸、醋酸、草酸等）当药物为阴离子时，则选用碱性缓冲剂（如碳酸钠、碳酸氢钠、磷酸钠、磷酸氢钠等）。
5、如权利要求3所述的三种脂质体的制剂的制备方法，其特征在于脂质体双层分子材料可选用磷脂酰胆碱、卵磷脂酰胆碱、豆磷脂酰胆碱、氢化豆磷脂酰胆碱、二月桂酰卵磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二鲸腊磷脂、二硬脂酰磷脂酰甘油、硫脂、胆固醇、粪甾醇、胆甾烷、胆甾烷醇、α-生育酚等，其总用量相当于喷雾干燥前脂质体溶液的0.5～15%，内、外层脂质比例约为1∶2∶其中磷脂与胆固醇的比例应在1∶0.2～1∶1之间，内层脂质层的胆固醇含量应比外层大些。
6、如权利要求3所述的三种脂质体的制剂的制备方法，其特征在于喷雾（蒸发）后W/O/W型复合乳的油层只剩下微量的豚脂或油凝胶，故形成了特殊的脂质体双分子层，此双分子层间的豚脂或油胶脂可有效地阻止水溶性药物的卸漏。其中油凝胶是由助悬剂如单、二、三硬脂酸铝等和油相如植物油、苄甲酸苄酯、油酸乙脂等构成的。豚脂或油凝胶与脂质体材料的比例应在0-500%之间，油凝胶中助悬剂的用量应是油相的0.5～5%。
7、如权利要求3所述的注射用缓释脂质体的制备方法，其特征在于要求3中②③脂质体所用高粘度聚合物可选用海藻酸钠、甲基纤维素、羧甲基纤维素、聚乙烯比各烷酮、支链淀粉及胶类等，其用量应视聚合物的种类，复溶后癌实体注射所需的缓释程度而定③喷雾干燥方法可将高粘度聚合物液体混合均匀后进行喷雾干燥法，也可两种液体由不同喷枪喷出同室进行喷雾干燥法。
8、如权利要求3所述的三种脂质体的制剂的制备方法，其特征在于含2/3脂质的外相水溶液在乳化W/O/W乳前应将PH调至7左右（略于内层水相PH相反即可），以便使制备W/O/W乳时漏出的部分药物在喷雾干燥时能回归内层水相。
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