CN102688202B - 一种替莫唑胺冻干制剂 - Google Patents
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Abstract
本发明涉及一种替莫唑胺冻干制剂，含有替莫唑胺活性成分，和至少一种足以溶解替莫唑胺的增溶剂。本发明中采取的增溶剂选自N(2)-L-丙氨酰-L-谷氨酰胺、甘氨酰谷氨酰胺、甘氨酰酪氨酸、门冬氨酸鸟氨酸或它们的混合物。采用本发明技术制备的替莫唑胺制剂，更好的增加了替莫唑胺的溶解性和溶液的稳定性，质量更稳定，使用更方便，而且制备方法简单，适合大规模生产。
Description
技术领域
本发明涉及的是一种替莫唑胺冻干制剂，属于药物制剂工艺技术领域。
背景技术
替莫唑胺(Temozolomide，商品名Temodar)化学名3，4-二氢-3-甲基-4-氧代咪唑并[5，1-d]-1，2，3，5-四嗪-8-酰胺，由Schering-Plough公司开发。1999年FDA批准其口服胶囊制剂，用于治疗成人胶质细胞瘤和黑色素瘤，特别是多形性胶质母细胞瘤或间变性星形细胞瘤的一线治疗。替莫唑胺的出现是治疗恶性神经胶质瘤的一大进展。
目前临床上只有口服替莫唑胺胶囊，虽然口服后完全吸收，生物利用度高，组织分布好，可透过血脑屏障，但其副作用恶心、呕吐、头痛和倦怠的发生率非常高，重度恶心和呕吐的发病率分别为10％和6％。由于恶心、呕吐造成药物吸收不全，通常在服药前要先服用止吐药，给患者带来极大的痛苦和经济负担，另外手术后病人常不适用固体药物，再加上传统临床用药习惯，替莫唑胺注射剂更适于临床使用。
替莫唑胺在水中微溶，在甲醇中极微溶解，在乙醇、丙酮或氯仿中几乎不溶，这一特性给替莫唑胺注射剂制备带来了很大的难度。
目前对替莫唑胺注射制剂的已公开的研究文献报道如下：
US6251886中公开了一种以微粒化的悬浮液形式给药的替莫唑胺注射剂，但会导致血管堵塞，是不理想的。
中国专利CN200510014962.3中公开了一种替莫唑胺冻干粉针剂，该制剂通过调节pH和加热超声使替莫唑胺溶解，但整个溶解配制过程时间长，替莫唑胺溶液不稳定，注射剂的使用存在质量安全隐患。
中国专利CN03804363.7中公开了一种替莫唑胺冻干粉针剂，该制剂含有替莫唑胺，以及至少一种足以溶解替莫唑胺的增溶剂，所述的增溶剂是脲、L-组氨酸，L-苏氨酸、天冬酰胺酸、丝氨酸、谷氨酰胺或它们的混合物。该冻干制剂方法缩短了替莫唑胺的溶解时间和增加了溶液的稳定性，但该制备方法存在溶解后形成的溶液还是易于析出固体，专利采用二次过滤的方法来解决此问题，但这种方法存在生产时间长、操作繁琐、造成主药浪费等诸多缺点，工业化生产难以实现。
发明内容
本发明的目的是提供一种或多种更好的增溶剂，增加替莫唑胺的溶解性和溶液的稳定性，克服现有技术的不足之处，提供一种替莫唑胺冻干制剂。采用本发明技术制备的替莫唑胺冻干制剂，质量更稳定，临床使用方便，而且制备方法简单，适合大规模生产。
本发明选用一种或多种二肽做为增溶剂，增加了替莫唑胺的溶解性和溶液的稳定性。二肽优选N(2)-L-丙氨酰-L-谷氨酰胺、甘氨酰谷氨酰胺、甘氨酰酪氨酸、门冬氨酸鸟氨酸或它们的混合物。实验证明，用二肽做增溶剂，溶解后形成的溶液稳定性好，不易析出晶体，溶液澄清。采用二肽做增溶剂，溶液稳定性好，减少了生产中二次过滤的步骤，缩短了生产时间，更利于制剂的工业化生产。
本发明提供的替莫唑胺冻干制剂，含有替莫唑胺活性成分，和至少一种足以溶解替莫唑胺的增溶剂。本发明中采取的增溶剂选自N(2)-L-丙氨酰-L-谷氨酰胺、甘氨酰谷氨酰胺、甘氨酰酪氨酸、门冬氨酸鸟氨酸或它们的混合物。其中替莫唑胺活性成分的重量百分比为1～50％。增溶剂的重量百分比为2～60％。
本发明提供的替莫唑胺冻干制剂，还包含至少一种赋形剂。本发明中采取的赋形剂选自聚山梨醇酯-20、聚山梨醇酯-80、聚乙二醇、丙二醇或它们的混合物，重量百分比为1～50％。
本发明提供的替莫唑胺冻干制剂，还包含至少一种填充剂。本发明中采取的填充剂选自甘露糖醇、海藻糖、右旋糖、乳糖、甘氨酸、蔗糖、羟乙基淀粉、纤维素、环糊精、氯化钠、淀粉或它们的混合物，重量百分比为20～80％。
本发明提供的替莫唑胺冻干制剂，还包含至少一种缓冲剂。本发明中采取的缓冲剂选自柠檬酸盐水合物或它们的混合物，重量百分比为5～60％。
本发明提供的替莫唑胺冻干制剂，还包含至少一种pH调节剂，选自盐酸、磷酸、乳酸、氢氧化钠、琥珀酸、柠檬酸、酒石酸或它们的混合物，重量百分比为1～20％。
本发明提供的替莫唑胺冻干制剂，还包含到水性稀释剂，选自水、生理盐水、5％的右旋糖溶液和它们的混合物。
本发明的替莫唑胺冻干制剂的制备方法，包括下列步骤，(1)先将增溶剂、赋形剂、填充剂、缓冲剂和pH调节剂完全溶于注射用水，再将替莫唑胺溶于其中，调节pH至3.0～6.0；(2)除菌过滤、灌装，冷冻干燥形成一种冻干制剂。
具体实施方式
下面通过实施例来进一步说明本发明，但本发明的内容完全不局限于些。
实施例1
制剂组成：
制备方法：
称取上述重量的N(2)-L-丙氨酰-L-谷氨酰胺、聚山梨酯80、甘露醇、枸橼酸钠、盐酸，加入8000ml注射用水中，搅拌至固体全部溶解澄清，加入处方量的替莫唑胺，搅拌至固体全部溶解澄清，用盐酸溶液或氢氧化钠溶液调节pH到5.0；加注射用水补足体积到10000ml，经0.22μm微孔滤膜除菌过滤，分装于30ml西林瓶中，每支分装10ml溶液，放于冻干箱，冷冻干燥形成一种冻干制剂。
实施例2
制剂组成：
制备方法：
称取上述重量的甘氨酰谷氨酰胺、聚山梨酯80、甘露醇、枸橼酸钠、盐酸，加入8000ml注射用水中，搅拌至固体全部溶解澄清，加入处方量的替莫唑胺，搅拌至固体全部溶解澄清，用盐酸溶液或氢氧化钠溶液调节pH到5.0；加注射用水补足体积到10000ml，经0.22μm微孔滤膜除菌过滤，分装于30ml西林瓶中，每支分装10ml溶液，放于冻干箱，冷冻干燥形成一种冻干制剂。
实施例3
制剂组成：
制备方法：
称取上述重量的甘氨酰酪氨酸、聚山梨酯80、甘露醇、枸橼酸钠、盐酸，加入8000ml注射用水中，搅拌至固体全部溶解澄清，加入处方量的替莫唑胺，搅拌至固体全部溶解澄清，用盐酸溶液或氢氧化钠溶液调节pH到5.0；加注射用水补足体积到10000ml，经0.22μm微孔滤膜除菌过滤，分装于30ml西林瓶中，每支分装10ml溶液，放于冻干箱，冷冻干燥形成一种冻干制剂。
实施例4
制剂组成：
制备方法：
称取上述重量的门冬氨酸鸟氨酸、聚山梨酯80、甘露醇、枸橼酸钠、盐酸，加入8000ml注射用水中，搅拌至固体全部溶解澄清，加入处方量的替莫唑胺，搅拌至固体全部溶解澄清，用盐酸溶液或氢氧化钠溶液调节pH到5.0；加注射用水补足体积到10000ml，经0.22μm微孔滤膜除菌过滤，分装于30ml西林瓶中，每支分装10ml溶液，放于冻干箱，冷冻干燥形成一种冻干制剂。
实施例5
考察实施例1～4制备的冻干制剂样品的稳定性。
实验条件：(25℃±2℃，RH60％±10％)
考察项目：有关物质、含量
测定频率：第0、3、6、9、12、18、24个月末取样测定
考察方法：参照中国药典2010版二部标准，
有关物质：采用高效液相色谱法，1％自身对照法测定
含量：采用高效液相色谱法，外标法测定
考察结论：实施例1～4制备的冻干制剂样品，在放置24个月后，含量和有关物质均未发生明显变化，说明实施例1～4制备的冻干制剂样品稳定性可靠。具体实验结果下表1。
表1实施例1～4冻干制剂样品中的稳定性实验结果
Claims (3)
1.一种替莫唑胺冻干制剂，含有替莫唑胺活性成分、和至少一种足以溶解替莫唑胺的增溶剂，增溶剂选自N(2)-L-丙氨酰-L-谷氨酰胺、甘氨酰谷氨酰胺、甘氨酰酪氨酸、门冬氨酸鸟氨酸或它们的混合物。
2.如权利要求1所述的冻干制剂，其特征在于，替莫唑胺活性成分的重量百分比为1～50％。
3.如权利要求1所述的冻干制剂，其特征在于，增溶剂的重量百分比为2～60％。
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