CN117815184A - 帕博西尼固体分散体、其制备方法及应用 - Google Patents
帕博西尼固体分散体、其制备方法及应用 Download PDFInfo
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- CN117815184A CN117815184A CN202311646230.0A CN202311646230A CN117815184A CN 117815184 A CN117815184 A CN 117815184A CN 202311646230 A CN202311646230 A CN 202311646230A CN 117815184 A CN117815184 A CN 117815184A
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Abstract
本发明提供了帕博西尼固体分散体、其制备方法及应用。本发明公开了一种帕博西尼固体分散体,其包括:帕博西尼原料药、高分子材料和小分子有机酸;所述的高分子材料包括聚乙烯醇聚乙二醇共聚物IR和聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect;所述的小分子有机酸包括枸橼酸、苹果酸、琥珀酸和酒石酸。本发明的帕博西尼固体分散体溶解度高、大大提高了该药物在高pH环境下的溶出度和溶出速率、临床前景好。
Description
本申请为2021年12月16日提交的,发明名称为“帕博西尼固体分散体、其制备方法及应用”的中国专利申请202111542821.4的分案申请。
本申请要求享有如下在先申请的优先权权益:2020年12月28日向中国国家知识产权局提交的申请号为202011578146.6的中国发明专利申请。上述在先申请的全文以引用的方式结合至本文。
技术领域
本发明涉及一种帕博西尼固体分散体、其制备方法及应用。
背景技术
帕博西尼(palbociclib)化学名为6-乙酰基-8-环戊基-5-甲基-2-[[5-(1-哌嗪基)-2-吡啶基]氨基]吡啶[2,3-d]嘧啶-7(8H)-酮(6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one),分子式:C24H29N7O2,分子量:447.54。
帕博西尼适用于激素受体(HR)阳性、人表皮生长因子受体2(HER2)阴性的局部晚期或转移性乳腺癌,应与芳香化酶抑制剂联合使用作为绝经后女性患者的初始内分泌治疗,其微溶于二甲基亚砜和二甲基甲酰胺,几乎不溶于甲醇和水。
帕博西尼在水溶液中的溶解度呈现明显的pH依赖性,帕博西尼易溶于pH低于4.0的介质中,当pH值高于pH4.0时,帕博西尼溶解度显著降低,帕博西尼的水中溶解度为(0.0174mg/mL-来源ALOGPS)。人体消化道pH在由胃内到肠道的阶段逐渐升高,导致药物服用后API在胃内溶解,胃排空后进入肠道内,因肠道环境pH较高,溶解的药物产生沉淀析出,故而降低了其生物利用度。因此,提高该药物在高pH环境下的溶出度,提高其生物利用度是目前继续解决的技术问题。
发明内容
本发明所要解决的技术问题是为了克服现有帕博西尼制剂溶出度不高、生物利用度不理想等缺陷而提供了一种与现有技术完全不同的帕博西尼固体分散体、其制备方法及应用。本发明的帕博西尼固体分散体溶解度高、大大提高了该药物在高pH环境下的溶出度和溶出速率、临床前景好。
本发明提供了一种帕博西尼固体分散体,其包括帕博西尼原料药、高分子材料和小分子有机酸;所述的高分子材料包括聚乙烯醇聚乙二醇共聚物IR(以下简称KollicoatIR)和聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect(以下简称KollicoatProtect);所述的小分子有机酸包括枸橼酸、苹果酸、琥珀酸和酒石酸。
本发明中,所述的帕博西尼原料药包括帕博西尼游离碱及其药用盐。
本发明中,所述的苹果酸包括L-苹果酸和D-苹果酸;所述的酒石酸包括L-酒石酸和D-酒石酸。
本发明中,所述的小分子有机酸可以采用其水溶液的形式使用,当所述的小分子有机酸采用水溶液的形式使用时,小分子有机酸水溶液的浓度优选1%~5%,例如2%,所述的百分比是指小分子有机酸的质量占小分子有机酸水溶液总质量的百分比。
本发明中,所述的帕博西尼与所述的Kollicoat Protect的质量比值可以为0.1~10.0,也可以为0.5~2.0,例如0.5、1.0或2.0。
本发明中,所述的帕博西尼与所述的Kollicoat IR的质量比值可以为0.1~10.0,也可以为0.5~2.0,例如0.5、1.0或2.0。
本发明中,所述的小分子酸与所述的帕博西尼的质量比值可以为0.1~10.0,也可以为0.5~2.0,例如1.6或2.0。
本发明中,所述的帕博西尼固体分散体,优选如下任一处方:
处方一:帕博西尼、Kollicoat Protect和枸橼酸;所述的枸橼酸:所述的Kollicoat Protect:所述的帕博西尼的质量比值可以为1.6:1.0:1.0、2.0:2.0:1.0、2.0:1.0:1.0或4.0:1.0:2.0。
处方二:帕博西尼、Kollicoat IR和枸橼酸;所述的枸橼酸:所述的Kollicoat IR:所述的帕博西尼的质量比值可以为2.0:2.0:1.0、4.0:1.0:2.0或2.0:1.0:1.0。
处方三:帕博西尼、Kollicoat Protect和L-苹果酸;所述的L-苹果酸:所述的Kollicoat Protect:所述的帕博西尼的质量比值可以为2.0:1.0:1.0。
处方四:帕博西尼、Kollicoat IR和L-苹果酸;所述的帕博西尼:Kollicoat IR的质量比值可以为2.0:1.0:1.0。
本发明还提供了所述的帕博西尼固体分散体的制备方法,其包括以下步骤:将小分子有机酸的水溶液与高分子载体混合溶清之后,再与帕博西尼原料药混合溶清、之后除去溶剂,干燥,得到所述的帕博西尼固体分散体即可。
所述的“小分子有机酸的水溶液”的质量浓度优选1%~5%,例如2%,所述的百分比是指小分子有机酸的质量占小分子有机酸水溶液总质量的百分比。
所述的“小分子有机酸的水溶液”的温度可以为30℃~50℃,例如45℃。
所述的除去溶剂优选采用减压除去溶剂或者鼓风干燥,所述的减压出去溶剂优选在旋转蒸发仪中进行。所述的鼓风干燥的温度可以为30℃~50℃,例如80℃、70℃或60℃;所述的鼓风干燥的时间可以为,例如14小时或15小时。
所述的干燥优选恒温鼓风干燥或者冷冻干燥;所述的冷冻干燥的温度优选-80℃~0℃,进一步优选-45℃~-35℃,例如-45℃~-40℃。所述的冷冻干燥的时间优选10小时~100小时,进一步优选30小时~50小时,例如39小时或36小时。所述的冷冻干燥的压强可以为1pa~100pa,例如15pa~25pa。
所述的冷冻干燥之前优选经过预冷冻,所述的预冷冻的温度优选-30℃~0℃,进一步优选-25℃~-5℃,例如-20℃。所述的预冷冻的时间优选1小时~10小时,进一步优选2小时~6小时,例如3小时。
所述的干燥优选冷冻干燥或者鼓风干燥。所述的鼓风干燥优选恒温鼓风干燥。所述的恒温鼓风干燥的温度优选20℃~100℃,进一步优选40℃~90℃,例如60℃、70℃或80℃。所述的恒温鼓风干燥的时间优选1小时~30小时,进一步优选2小时~20小时,例如14小时或15小时。
所述的冷冻干燥的温度优选-80℃~0℃,进一步优选-70℃~-5℃,例如-40℃~-45℃。所述的冷冻干燥的时间优选1小时~50小时,进一步优选20小时~40小时,例如36小时。所述的冷冻干燥的压强优选1pa~100pa,例如15pa~25pa。
本发明还提供了所述的帕博西尼固体分散体的制备方法,其优选包括以下步骤:30℃~50℃下,将小分子有机酸水溶液,与高分子材料混合,待载体溶清后,再与帕博西尼原料药混合,搅拌至溶清,然后除去大部分溶剂至溶液呈浸膏装,冷冻干燥或于恒温鼓风干燥,即得帕博西尼固体分散体。
本发明还提供了所述的帕博西尼固体分散体在制备帕博西尼药物制剂中的用途。所述的药物制剂可以为片剂、胶囊剂、丸剂、粉剂、颗粒剂或栓剂。
本发明还提供了所述的帕博西尼固体分散体在制备治疗和/或预防哺乳动物由异常细胞增殖引起的障碍或病症、感染引起的障碍或病症、阿尔兹海默症、牛皮癣、炎症、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎、器官移植排斥的疾病的药物中的用途。
所述的哺乳动物由异常细胞增殖引起的障碍或病症选自癌症、与动脉粥样硬化有关的血管平滑肌增生和手术后血管狭窄和再狭窄以及子宫内膜异位。
所述的癌症选自乳腺癌、卵巢癌、子宫颈癌、前列腺癌、睾丸癌、食道癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、颊腔与咽癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病。
所述的感染选自病毒感染和真菌感染。
所述的器官移植排斥包括宿主对移植物。
所述的帕博西尼固体分散体的用量为有效治疗这类障碍或疾病的量给予所述哺乳动物。
本发明的积极进步效果在于:本发明制备的不同载体及药载比的帕博西尼固体分散体在高pH环境(pH6.8磷酸水溶液)中表现出了显著的增溶作用,125mg规格的帕博西尼固体分散体在体积为900ml的pH6.8磷酸盐缓冲液中,采用USP第二法转速50rpm进行溶出实验,5分钟即可溶出完全;采用相同组分及比例配制的规格为125mg的帕博西尼物理混合物在同条件下的90分钟的溶出度不及40%。此外,本发明制备的不同载体及药载比的帕博西尼固体分散体在pH6.8磷酸盐缓冲液的饱和溶解度显著提高。本发明的制备方法采用冷冻干燥,操作简单,制得的固体分散体呈蓬松状,易收集和进一步处理,市场化前景好。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
根据本发明的实施方案,所述的室温是指环境温度为10℃~35℃。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1:
帕博西尼:Kollicoat Protect=1:1(m/m),所用小分子有机酸为枸橼酸,枸橼酸水溶液浓度为2%(m/m),此处枸橼酸水溶液配制方法为量取500g纯化水,加入10g枸橼酸。
取处方量的2%(m/m)枸橼酸水溶液,置于烧杯中,依次加入处方量的KollicoatProtect、帕博西尼,此处枸橼酸:Kollicoat Protect:帕博西尼约为1.6:1:1(m/m/m),室温搅拌至完全溶清后转移至表面皿中。将表面皿置于80℃恒温鼓风干燥箱中干燥3h挥去大部分溶剂后,置于60℃鼓风干燥箱中干燥15h即得。
实施例2:
帕博西尼:Kollicoat Protect=1:1(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat Protect、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat Protect:帕博西尼约为2:1:1(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至25rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将旋蒸后的溶液快速铺展在直径约15cm的表面皿中,将表面皿置于70℃恒温鼓风干燥箱中干燥14h即得。
实施例3:
帕博西尼:Kollicoat IR=1:1(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat IR、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat IR:帕博西尼约为2:1:1(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至25rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例4:
帕博西尼:Kollicoat Protect=1:2(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat Protect、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat Protect:帕博西尼约为2:2:1(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例5:
帕博西尼:Kollicoat IR=1:2(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat IR、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat IR:帕博西尼约为2:2:1(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例6:
帕博西尼:Kollicoat Protect=2:1(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat Protect、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat Protect:帕博西尼约为4:1:2(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例7:
帕博西尼:Kollicoat IR=2:1(m/m),所用小分子有机酸为枸橼酸。
取处方量的纯化水置于烧杯中,依次加入处方量的枸橼酸、Kollicoat IR、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处枸橼酸:Kollicoat IR:帕博西尼约为4:1:2(m/m/m),枸橼酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例8:
帕博西尼:Kollicoat IR=1:1(m/m),所用小分子有机酸为L-苹果酸。
取处方量的纯化水置于烧杯中,依次加入处方量的L-苹果酸、Kollicoat IR、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处L-苹果酸:Kollicoat IR:帕博西尼约为2:1:1(m/m/m),L-苹果酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实施例9:
帕博西尼:Kollicoat Protect=1:1(m/m),所用小分子有机酸为L-苹果酸。
取处方量的纯化水置于烧杯中,依次加入处方量的L-苹果酸、KollicoatProtect、帕博西尼,常温搅拌至完全溶清后转移至梨形蒸发瓶中,此处L-苹果酸:Kollicoat Protect:帕博西尼约为2:1:1(m/m/m),L-苹果酸水溶液浓度约为2%(m/m)。
打开循环冷却液反应浴,进行冷却液制冷循环;关闭旋转蒸发仪气阀,水浴温度设置为60℃,转速设置为15rpm(后续增速至50rpm),旋蒸至梨形蒸发瓶种溶液呈浸膏状。
将溶液快速铺展于表面皿中,放置于-20℃冰箱预冻3小时后,将样品放置于冷冻干燥机中冻干约36h,冻干温度-40℃~-45℃,真空15pa~25pa。
实例2-3和实施例8-9帕博西尼固体分散体在在体积为900ml的pH6.8磷酸盐缓冲液中,采用USP第二法转速50rpm进行溶出实验,固体分散体规格为125mg,同时以相同组分及比例配制的同规格帕博西尼物理混合物在同条件下的溶出结果作为参照。溶出结果见表1。
实例4-7帕博西尼固体分散体在在体积为900ml的pH6.8磷酸盐缓冲液中,采用USP第二法转速50rpm进行溶出实验,固体分散体规格为125mg,溶出结果见表2。
实施例1-9帕博西尼固体分散体在pH6.8磷酸盐缓冲液中饱和溶解度结果及帕博西尼原料药在各pH介质中的饱和溶解度见表3和表4。
表1-帕博西尼固体分散体及等比例物理混合物在pH6.8介质溶出
表2-帕博西尼固体分散体在pH6.8介质溶出
表3-帕博西尼固体分散体在pH6.8磷酸盐缓冲液中的饱和溶解度
表4-帕博西尼原料药在不同pH介质中的饱和溶解度
介质种类 | 溶解度(mg/ml) |
水 | 0.0133 |
pH1.0盐酸溶液 | 23.26 |
pH4.5醋酸盐缓冲液 | 9.37 |
pH6.8磷酸盐缓冲液 | 0.03 |
2%(m/v)枸橼酸水溶液(pH2.0) | 20.20 |
由表1~表4结果可见,本发明自制帕博西尼固体分散体在高pH环境中的溶解度得到了显著的提高。
Claims (11)
1.一种帕博西尼固体分散体,其特征在于其包括:帕博西尼原料药、高分子材料和小分子有机酸;所述的高分子材料包括聚乙烯醇聚乙二醇共聚物IR和聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect;所述的小分子有机酸包括枸橼酸、苹果酸、琥珀酸和酒石酸。
2.如权利要求1所述的帕博西尼固体分散体,其特征在于:所述的帕博西尼原料药包括帕博西尼游离碱及其药用盐;所述的苹果酸包括L-苹果酸和D-苹果酸;所述的酒石酸包括L-酒石酸和D-酒石酸。
3.如权利要求1所述的帕博西尼固体分散体,其特征在于:所述的帕博西尼与所述的Kollicoat Protect的质量比值为0.1~10.0;
和/或,
所述的帕博西尼与所述的Kollicoat IR的质量比值为0.1~10.0;
和/或,
所述的小分子酸与所述的帕博西尼的质量比值为0.1~10.0。
4.如权利要求3所述的帕博西尼固体分散体,其特征在于:所述的帕博西尼与所述的Kollicoat Protect的质量比值为0.5~2.0;
和/或,
所述的帕博西尼与所述的Kollicoat IR的质量比值为0.5~2.0;
和/或,
所述的小分子酸与所述的帕博西尼的质量比值为0.5~2.0。
5.如权利要求1所述的帕博西尼固体分散体,其特征在于:所述的帕博西尼固体分散体,为如下任一处方:
处方一:帕博西尼、聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect和枸橼酸;所述的枸橼酸:所述的聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect:所述的帕博西尼的质量比值为1.6:1.0:1.0、2.0:2.0:1.0、2.0:1.0:1.0或4.0:1.0:2.0;
处方二:帕博西尼、聚乙烯醇聚乙二醇共聚物IR和枸橼酸;所述的枸橼酸:所述的聚乙烯醇聚乙二醇共聚物IR:所述的帕博西尼的质量比值为2.0:2.0:1.0、4.0:1.0:2.0或2.0:1.0:1.0;
处方三:帕博西尼、聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect和L-苹果酸;所述的L-苹果酸:所述的聚乙烯醇聚乙二醇共聚物与聚乙烯醇混合物Protect:所述的帕博西尼的质量比值为2.0:1.0:1.0;
处方四:帕博西尼、聚乙烯醇聚乙二醇共聚物IR和L-苹果酸;所述的L-苹果酸:所述的聚乙烯醇聚乙二醇共聚物IR:所述的帕博西尼的质量比值为2.0:1.0:1.0。
6.如权利要求1~5任一项所述的帕博西尼固体分散体的制备方法,其特征在于包括以下步骤:将小分子有机酸的水溶液与高分子载体混合溶清之后,再与帕博西尼原料药混合溶清、之后除去溶剂,干燥,得到所述的帕博西尼固体分散体即可。
7.如权利要求1~5任一项所述的帕博西尼固体分散体在制备帕博西尼药物制剂中的用途。
8.如权利要求7所述的用途,其特征在于:所述的药物制剂为片剂、胶囊剂、丸剂、粉剂、颗粒剂或栓剂。
9.如权利要求1~5任一项所述的帕博西尼固体分散体在制备治疗和/或预防的哺乳动物由异常细胞增殖引起的障碍或病症、感染引起的障碍或病症、阿尔兹海默症、牛皮癣、炎症、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎、器官移植排斥的疾病的药物中的用途。
10.如权利要求9所述的用途,其特征在于:所述的哺乳动物由异常细胞增殖引起的障碍或病症选自癌症、与动脉粥样硬化有关的血管平滑肌增生和手术后血管狭窄和再狭窄以及子宫内膜异位。
11.如权利要求10所述的帕博西尼固体分散体,其特征在于:所述的癌症选自乳腺癌、卵巢癌、子宫颈癌、前列腺癌、睾丸癌、食道癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、颊腔与咽癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病;
所述的感染选自病毒感染和真菌感染;
所述的器官移植排斥包括宿主对移植物。
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