CN1058391C - 已制成的可用的注射用蒽环苷类抗癌剂的溶液 - Google Patents

已制成的可用的注射用蒽环苷类抗癌剂的溶液 Download PDF

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CN1058391C
CN1058391C CN87108225A CN87108225A CN1058391C CN 1058391 C CN1058391 C CN 1058391C CN 87108225 A CN87108225 A CN 87108225A CN 87108225 A CN87108225 A CN 87108225A CN 1058391 C CN1058391 C CN 1058391C
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加埃塔诺·加蒂
迪耶戈·奥尔达尼
朱塞佩·博托尼
卡洛·孔法洛涅里
卢恰诺·甘比尼
罗伯托·德蓬蒂
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Abstract

一种贮存稳定、无菌的、无热原的可注射用蒽环苷类溶液。此溶液基本上是由一种蒽环苷的生理上可接受的盐溶解在一种生理上可以接受的溶媒所组成，它不是由冻干制剂重新配制而成的，其pH已调至2.5-4.0。

Description

已制成的可用的注射用蒽环苷类抗癌剂的溶液
本发明是关于一种贮存稳定、已制成的即可使用的注射用蒽环苷类抗肿瘤药(如阿霉素)的溶液及此溶液的制备方法。
蒽环苷类化合物是在抗癌剂中已熟知的一类化合物(其中阿霉素是典型的)，应用最广。代表化合物：阿霉素。抗肿瘤抗生素Fed-erico Arcamone，1981，出版：Academic Press，NewYork，N.Y.；阿霉素综述EROTC国际专题论文集Brussels，1974年5月，M.Staguet编，Eur.Press Medikon出版，Ghent.Belg.；阿霉素临床结果，阿霉素专题论文集法兰克福/梅因1974，M.Ghione，J.Fetzer及H.Maier编、Springer出版，New York，N.Y.
目前，蒽环苷类抗癌剂，特别是如阿霉素，只能得到冻干制剂形式，在给药前需重新配制。这些制剂的制造和重新配制使得参予的人员(工人、药师、医务人员、护士)冒污染的危险，这样，由于抗癌药物的毒性，使得这种污染就特别严重了。
马尔丁代大药典第28版第175页左栏报导了抗肿瘤药物的副作用，并建议“它们在使用时必须十分小心，避免与皮肤和眼睛接触，不能吸入。必须小心，不要溢出，以免发生疼痛和组织损坏。”同样，在瑞士工作环境卫生杂誌第10卷(2)，第71-74页(1984)上，以及“化学工业”7月4日(1983)出版，第488页，Drng-Topics-Medical-Economics-Co，2月7日出版(1983)，第99页上的文章都报告了在使用抗癌剂(包括阿霉素)的医务人员身上观察到的严重的副作用。
冻干制剂的给药，需要将此药物处理两次。首先，必须将冻干饼重新配制，然后给药。因为溶解的问题，有时可能要长时间的振摇以便完全溶解。重新配制冻干饼或粉末可导致形成气雾小滴，而这可使配制该溶液的操作人员吸入或使其度肤或粘膜相接触。
如果能得到已制成的即可使用的药物溶液，与制备和重新配制这冻干制剂有关的这种危险就将大大减小。我们已经开发出了一种稳定的、可用于临床静脉注射的蒽环苷类(如阿霉素)药物的溶液，而这种溶液的制备与给药均不需冻干和重新配制。
GB-A-2,178,311阐述并申请了无菌的、无热原的蒽环苷溶液的专利，其本质是一个蒽环苷类(如阿霉素)的生理上可接受的盐(溶解在一个生理上可接受的溶媒中的溶液。因此它未经从冻干制剂重新配制，其pH是2.5-6.5。较好的pH是约3和5。其举例说明的pH范围是2.62-3.14、4.6和5.2。未提及稳定剂。提到葡萄糖、乳糖和甘露糖醇作为张力调节剂，但未提到它们可以使用的比例。
我们现在发现，此溶液在pH2.5-4.0时稳定性较好。因此本发明提供了一贮存稳定的、无菌的、无热原的注射用的蒽环苷溶液。其本质是蒽环苷的生理上可接受的盐溶解在生理上可接受的溶媒中的溶液，因此它未经从冻干制剂重新配制，而其pH已调节至2.5-4.0。
这样就可以提供贮存稳定并具有商业意义的贮存期的溶液。
本发明的溶液最好在一封闭的容器中供应，特别是玻璃容器。此溶液可以由单一剂量的形式供应，也可以是多剂量的形式。
最好此蒽环苷选自阿霉素、4′-表-阿霉素(即表阿霉素)、4′-脱氧-阿霉素、4′-脱氧-4′-碘-阿霉素、柔红霉素和4-去甲氧柔红霉素(即去甲正定霉素)、最佳的蒽环苷是阿霉素。
任何一种的蒽环苷的生理上可接受的盐均可用作制备本发明的溶液。适宜的盐的例子可以是，无机酸如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐、一些有机酸如乙酸、琥珀酸、酒石酸、抗坏血酸、柠檬酸、谷氨酸、苯甲酸、甲磺酸、乙磺酸等的盐。盐酸盐是最佳的盐，特别是当蒽环苷是阿霉素时。
任何一种生理上可以接受的、可以溶解蒽环苷的溶媒均可以使用。本发明的溶液也可以含有一种或多种处方辅助剂如共溶剂(它可以同样是溶媒)、稳定剂、张力调节剂、防腐剂和可供药用的螯合剂。
适宜的溶媒和共溶剂可以是，如水，如注射用水、0.9％氯化钠溶液即生理盐水、5％葡萄糖溶液、脂肪族酰胺类如N，N-二甲基乙酰胺、N-羟基-2-乙基-乳酰胺等、醇类如乙醇、苄醇等、二元醇类和多元醇类如丙二醇、甘油等、多元醇酯类如甘油二乙酸酯、甘油三乙酸酯等、聚二醇类和聚醚类如聚乙二醇400、丙二醇甲醚等、二氧戊烷类如异亚丙基甘油等、异山梨醇二甲酯、吡略烷酮衍生物如2-吡咯烷酮、N-甲基-2-吡咯烷酮、聚乙烯吡咯烷酮(仅作共溶剂)等、聚氧乙烯化的脂肪醇如Brij(商标)等、聚氧乙烯化的脂肪酸类酯类如Cremophor(商标)、Myrj(商标)等、聚缩山梨醇油酸酯如吐温(商标)、聚丙二醇类的聚氧乙烯衍生物如Pluronics(商标)。
较好的溶媒的例子是水、生理盐水、5％葡萄糖水溶液、乙醇、聚乙二醇和二甲基乙酰胺，以及这些溶媒各种比例的混合物。最好的是水、生理盐水和5％葡萄糖溶液。
最好的共溶剂是聚乙烯吡咯烷酮。
糖或糖醇可以作为稳定剂存在。适宜的稳定剂包括糖类如单糖类(如葡萄糖、半乳糖、果糖和岩藻糖)、二糖类(如乳糖)、多糖类(如右旋糖酐)和环状低聚糖(如α-、β-或γ-环糊精)、和单或多羟基脂肪醇，包括环状多元醇(如甘露糖醇、山梨糖醇、甘油、硫代甘油、乙醇和肌醇)。稳定剂在溶液中的浓度的从0.25-10％(W/V)，最好是0.5-5％W/V。
糖和糖醇也可用作张力调节剂。适宜的张力调节剂可包括如生理上可接受的无机氯化物。如氯化钠(最好是0.9％(重量)氯化钠)、葡萄糖、乳糖、甘露糖醇、山梨糖醇等。当糖或糖醇如葡萄糖、乳糖甘露糖醇或山梨糖醇存在时，以用2.5-7.5％(重量)为宜，4-6％(重量)更好，最好是5％(重量)。
生理上可以接受的防腐剂是，如对羟基苯甲酸酯(如其甲基、乙基、丙基和丁基酯，或它们的混合物)、氯甲酚等。
制药上可以接受的适宜的螯合剂可以是乙二胺四乙酸(EDTA)，所用的螯合剂量很小，典型的是从0.001-0.05％(重量)。
上面提到的溶媒、共溶剂、稳定剂、张力调节剂、防腐剂和螯合剂，可以单独使用，或者用它们的两种或多种的混合物。
为将pH调至2.5-4.0范围之内，可根据需要加入生理上可以接受的酸或缓冲剂。酸可以是生理上可以接受的任何一种，如无机酸，盐酸、氢溴酸、硫酸、磷酸、硝酸等、或有机酸如乙酸、琥珀酸、酒石酸、抗坏血酸、枸橼酸、谷氨酸、苯甲酸、甲磺酸、乙磺酸等，或者生理上可以接受的酸性缓冲溶液，如氯化物缓冲液、甘氨酸缓冲液、甲酸盐缓冲液、乙酸盐缓冲液、磷酸盐缓冲液等。
对本发明的已制成的即可使用的溶液的较好的pH范围是从2.5(如约2.6)到约3.7(如约3.5)。更好的pH范围是约3-3.5。当本发明的溶液含有山梨糖醇或2.5-7.5％(重量)葡萄糖、乳糖或甘露糖醇时，最好的pH是约3。其他的较好的pH范围是从大于3.14(如约3.2)到4(最好是到约3.7)，到约3.5更好。一种pH2.62-3.14的很有用的溶液还含有：
(i)0.25-10％(W/V)稳定剂和/或张度调节剂，它们选自糖类和单、多羟基脂肪醇。假定它们是葡萄糖、甘露糖醇或乳糖，其含量是2.5-7.5％(重量)；和或
(ii)可供药用的螯合剂。
在本发明的溶液中，蒽环苷的浓度变化范围很宽，可从0.1毫克/毫升至100毫克/毫升，特别是0.1毫克/毫升至50毫克/毫升，最好是1毫克/毫升至20毫克/毫升。
不同的蒽环苷的较适宜的浓度范围可能略有不同。如阿霉素的适宜浓度为2毫克/毫升至50毫克/毫升，2毫克/毫升至20毫克/毫升更好，最适宜的值是2毫克/毫升和5毫克/毫升。这种类似浓度也适合于4′-表阿霉素、4′-脱氧阿霉素和4′-脱氧-4′-碘-阿霉素。柔红霉素和4-去甲氧基柔红霉素的适宜浓度是0.1毫克/毫升至50毫克/毫升，1毫克/毫升至20毫克/毫升更好，1毫克/毫升和5毫克/毫升的浓度最适宜。
所有的已被允许用于胃肠道外给药的容器，如塑料及玻璃容器、注射用容器等均是蒽环苷溶液的适宜包装。较合适的容器是密封的玻璃容器，如小瓶或安瓶。密封的玻璃小瓶最适宜。
本发明还提供制造本发明的贮存稳定、无菌、无热原的可供注射的蒽环苷溶液的方法。此方法包括：(i)将蒽环苷的生理上可接受的盐溶解在生理上可以接受的溶媒中，此盐不是冻干形式的；(ii)亦可加入一种或多种处方辅助剂，如共溶剂、稳定剂、张度调节剂、防腐剂和可供药用的螯合剂。(iii)加入生理上可接受的酸或缓冲液，将pH调至所要求的2.5-4.0。此过程要求制成的溶液是无菌和无热原的。
能保证制成的溶液是无菌的和无热原的任何一种方法都可以采用。虽然所用的一种或多种物料可能是无菌的无热原的，但是，在(iii)步之后最好是将此溶液通过一下无菌过滤器。如果所用的物料均是无菌无热原的，那么也可能没有必要将制成的溶液通过无菌过滤器。
由本发明的溶液可以制得具有很高浓度蒽环苷活性物质的组合物，甚至达到50毫克/毫升或更高。这一点与现有的冷冻干燥制剂相比就有巨大的优越性。由于在再配制时的溶解的问题，冻干制剂配制高浓度的蒽环苷溶液就很困难，尤其是用生理盐水配制时。辅助剂(如乳糖)在冻干饼中与活性物质相比，一般含量比例较高，每份活性物质甚至含高达5份辅助剂。这些辅助剂对于溶解有负作用，致使在溶解冻干饼时，特别是在蒽环苷的浓度大于2毫克/毫升时，可能有困难。
本发明的溶液的特点是稳定性好。已经发现，在存放药物制剂可接受的温度下，各种溶媒和不同pH和浓度的溶液长期存放是稳定的。这一点在下面的例子中有说明。
蒽环苷活性药物的抗肿瘤活性是已熟知的，本发明的药物组合物对治疗人和动物宿主的肿瘤有效。可以治疗的肿瘤的例子有，例如肉瘤(包括骨骼及软组织肉瘤)、癌(如胸、肺、膀胱、甲状腺、前列腺和卵巢癌)、淋巴瘤(包括何杰金氏和非何杰金氏淋巴瘤)、或神经细胞瘤、黑素瘤、骨髓瘤、维尔姆斯氏瘤和白血病(包括急性淋巴性白血症和急性原始粒细胞性白血病)。
可以治疗的具体的肿瘤例子是莫洛尼氏(Moloney)肉瘤病毒、肉瘤180腹水、实体肉瘤180、巨型可移植型白血症(Gross tran-splantable leukemia)、L1210白血症和淋巴性P388白血症。
为抑制肿瘤的生长，特别是上述的肿瘤，可以通过对上述肿瘤的患者给以含足够量活性药物的本发明的可供注射溶液。以抑制上述肿瘤的生长。
本发明的可供注射的溶液的给药可以是快速的如静脉注射，或根据各种可能的剂量方案输注。
阿霉素的适宜的剂量方案可以是例如一次迅速输注60-75毫克活性药物/米2体表面积，并在21天重复。另一个方案是每28天静脉给药30毫克/米2·日，共3日，。4′-表-阿霉素和4′-脱氧阿霉素的适宜剂量可以是75-90毫克/米2一次输注，在21天重复。4′-脱氧-4′-碘-阿霉素可用相似的剂量方案。
去甲氧正定霉素，即去甲氧基柔红霉素在治疗实体肿瘤时，每21日一次静脉注射给药13-15毫克/米2，而在治疗白血病时，较好的剂量方案是例如静脉给药10-12毫克/米2·日，共三日，每15-21日重复。柔红霉素也可按相似的剂量方案给药。
下面的例子是本发明的说明。在附表中“E+3”表示“×103”，“d”是“日”。
图1是阿霉素盐酸盐在55℃无菌水中在不同pH下的降解(Kobs-PH)图(例1)；
图2是阿霉素盐酸盐在55℃5％葡萄糖中不同pH下的降解(Kobs-PH)图(例1)；
图3是阿霉素盐酸盐在55℃0.9％(生理)盐水中不同pH下的降解解(Kobs-PH)图(例1)；
图4是表阿霉素盐酸盐在55℃在无菌水(注射用水)中不同PH下的降解(Kobs-PH)图(例7)；
图5是表阿霉素盐酸盐在55℃在0.9％(生理)盐水中不同pH下的降解(Kobs-pH)图(例7)；
图6是阿霉素盐酸盐在55℃在5％葡萄糖中不同pH下的降解(Kobs-pH)图(例7)。
例1.阿霉素盐酸盐在55℃下，在无菌水、5％葡萄糖或0.9％盐
水中pH一稳定性表
将阿霉素盐酸盐溶解在下述I＝0.05缓冲液中，浓度是2毫克/毫升：
(a)甘氨酸-盐酸      pH2.0、2.5和3.0；
(b)甲酸盐           pH3.5；
(c)乙酸盐           pH4.0、5.0和5.5；
各溶液在氮气压下通过0.22μm微孔薄膜。各5.0毫升的溶液存放在最高容量8毫升的I型玻璃的玻璃小瓶中，聚四氟乙烯(Teflon商标)涂面的氯丁橡胶塞、铝封盖。各溶液按预定的时间(可高达120小时)测定阿霉素盐酸盐和pH。结果列在表1、2和3中，分别表示阿霉素盐酸盐在55℃、在无菌水、5％葡萄糖和0.9％盐水中，在不同pH和贮存时间下的残余浓度和百分稳定性。
阿霉素盐酸盐的测定是按美国药典〔美国药典高效液相色谱(HPLC)法(USP XXI)〕三次独立测定的平均值。在每个pH值下，
降解的假—一级速率常数(kobs)是由阿霉素盐酸盐的残余浓度(|DX|t)的自然对数对时间的线性回归分析计算得到，如下式所示
Ln|DX|t＝Ln|DX|o-Kobs·t
表4，5和6分别给出阿霉素盐酸盐在55℃，在不同pH下，在无菌水、5％葡萄糖和0.9％盐水溶液中观察到的降解动力学的速度常数(Kobs)。附图1、2和3表示阿霉素盐酸盐在55℃在上述介质中降解的Kobs-pH关系。
在表1-6和图1-3中的数据表明，2毫克/毫升阿霉素盐酸盐在所有三种受试介质中的溶液中，在pH2.5-4.0显示出在55℃下有良好的稳定性，在pH3.0-3.5下有最大的稳定性。由于在无菌水中或在含张度调节剂(离子型的如氯化钠，或非离子型的如葡萄糖)无菌水中，没有观察到稳定性的实际上的差别，因此，关于稳定性的共同规律一般是用在水溶液中来表明。表1-2毫克/毫升阿霉素盐酸盐在无菌水中的溶液，在不同的PH下加速(55℃)稳定性数据缓冲                                    时间(小时)液    试验              0        8      16     24     48    72      120pH     阿霉素盐酸2.0    盐分析          2.022   1.892   1.669 1.554  1.145  0.801甘氨酸·毫克/毫升      100.0   93.6    82.6  76.9   56.6   39.6-盐酸 ·稳定性％       2.00    2.01    2.02  2.01   2.01   2.02
   pH
   阿霉素盐酸pH     盐分析          1.992   1.926   1.835 1.718  1.557  1.002.5    ·毫克/毫升     100.0   96.7    92.1  86.2   78.2   50.2甘氨酸 ·稳定性％-盐酸   pH             2.51    2.50    2.50  2.52   2.51   2.52pH      阿霉素盐酸3.0     盐分析         2.003   1.958   1.881 1.831  1.696  1.525   1.258甘氨酸  ·毫克/毫升    100.0   97.8    93.9  91.4   84.7   76.1    62.8-盐酸   ·稳定性％     3.00    3.03    3.02  3.02   3.01   3.02    3.00
    pH
    阿霉素盐酸pH      盐分析         2.035   1.950   1.887 1.840  1.650  1.538   1.2413.5     ·毫克/毫升    100.0   95.8    92.7  90.4   81.1   75.6    61.0甲酸盐  ·稳定性％     3.51    3.51    3.51  3.51   3.52   3.52    3.51
    PH
    阿霉素盐酸pH      盐分析         2.032   1.788   1.681 1.561  1.1674.0     ·毫克/毫升    100.0   88.0    82.7  76.8   57.4乙酸盐  ·稳定性％     4.00    4.00    4.04  4.02   4.02
    PH
    阿霉素盐酸pH      盐分析         2.019   1.823   1.688 1.512  1.0605.0     ·毫克/毫升    100.0   90.3    83.6  74.9   52.5乙酸盐  ·稳定性％     5.03    5.05    5.04  5.04   5.05
    PH
    阿霉素盐酸pH      盐分析         2.047    1.808  1.427 1.228  0.9035.5     ·毫克/毫升    100.0    88.3   69.7  60.0   44.1乙酸盐  ·稳定性％     5.50     5.53   5.53  5.54   5.56
     PH
表2-2毫克/毫升阿霉素盐酸盐在5％葡萄糖中的溶液在不同PH下加速(55℃)稳定性数据
                                          时       间         (小时)缓冲液    试  验-             0      8       16      24      34      48      72      96      120
      阿霉素盐酸盐分析pH2.0     ·毫克/毫升        1.993  1.851   1.683  1.513    1.361  1.078   0.765甘氨酸-   ·稳定性％         100.0  92.8    84.4   75.9     68.3   54.1    38.4盐酸      PH                 2.14   2.13    2.14   2.15     2.18   2.21    2.16
      阿霉素盐酸盐分析pH 2.5    ·毫克/毫升        1.967  1.897   1.822  1.760    1.682  1.499   1.305甘氨酸-   ·稳定性％         100.0  96.4    92.6   89.5     85.5   76.2    66.3盐酸      PH                 2.56   2.56    2.56   2.58     2.60   2.56    2.61
      阿霉素盐酸盐分析pH 3.0   ·毫克/毫升         1.975          1.908  1.832           1.645   1.508  1.344    1.206甘氨酸-  ·稳定性％          100.0          96.6   92.7            83.3    76.4   68.0     61.1盐酸      PH                 3.04           3.05   3.05            3.06    3.00   3.13     3.10
      阿霉素盐酸盐分析pH3.5    ·毫克/毫升         1.983          1.897  1.858           1.622   1.324  1.222甲酸盐   ·稳定性％          100.0          95.7   93.7            81.8    66.8   61.6
      PH                  3.58           3.59   3.60            3.63    3.60   3.63
表2-2毫克/毫升阿霉素盐酸盐在5％葡萄糖中的溶液在不同PH下加速(55℃)稳定性数据(续)
                                    时      间       (小时)缓冲液    试    验             0       8    16      24      34    48          72        96    120
     阿霉素盐酸盐分析pH4.0    ·毫克/毫升          2.003  1.913  1.716  1.665  1.487  1.312       1.081乙酸盐   ·稳定性％           100.0  95.5   85.6   83.1   74.2   65.5        53.9
     pH                   4.10   4.10   4.11   4.11   4.16   4.15        4.12
     阿霉素盐酸盐分析pH5.0    ·毫克/毫升          2.012  1.906  1.673  1.608  1.416  1.163乙酸盐   ·稳定性％           100.0  94.7   83.2   79.9   70.4   57.8
     pH                   5.06   5.06   5.06   5.06   5.07   5.04
     阿霉素盐酸盐分析pH 5.5   ·毫克/毫升          1.991  1.841  1.470  1.246  1.091乙酸盐   ·稳定性％           100.0  92.5   73.8   62.6   54.8
     PH                   5.56   5.54   5.48   5.50   5.46
表3-2毫克/毫升阿霉素盐酸盐在0.9％盐水中的溶液在各种pH下加速(55℃)稳定性数据
                                                时      间      (小时)缓冲液     试  验               0      4      8      16      24      34      48      72      96      120
       阿霉素盐酸盐测定pH         ·毫克/毫升        1.998         1.857  1.580   1.397   1.231    0.931   0.7012.0        ·稳定性％         100.0         92.9   79.1    69.9    61.6     46.6    35.1甘氨酸     PH                 2.16          2.16   2.18    2.16    2.22     2.20    2.19
       阿霉素盐酸盐测定PH2.5      ·毫克/毫升        1.946         1.875  1.670   1.602   1.368    1.132甘氨酸     ·稳定性％         100.0         96.3   85.8    82.3    70.3     58.1-盐酸      PH                 2.59          2.59   2.59    2.58    2.62     2.62
       阿霉素盐酸盐测定pH3.0      ·毫克/毫升       1.994                1.818   1.771            1.571   1.375    1.205    1.003甘氨酸     ·稳定性％         100.0                91.2    88.8             78.8    69.0     60.4     50.3-盐酸      PH                 3.06                 3.07    3.07             3.08    3.13     3.14     3.12
       阿霉素盐酸盐测定PH3.5      ·毫克/毫升        1.997                1.824   1.742            1.543   1.323    1.176    0.919甲酸盐     ·稳定性％         100.0                91.4    87.2             77.3    66.2     58.9     46.0
       PH                 3.58                 3.56    3.56             3.66    3.61     3.64     3.63
       阿霉素盐酸盐测定PH4.0      ·毫克/毫升        1.972  1.885  1.828  1.653   1.594乙酸盐     ·稳定性％         100.0  95.6   92.7   83.8    80.8
       PH                 4.10   4.10   4.10   4.10    4.11
表3-2毫克/毫升阿霉素盐酸盐在0.9％盐水中的溶液在各种pH下加速(55℃)稳定性数据(续)
                                       时        间  (小时)缓冲液     试  验                   0      4       8       16     24     34    48     72      96      120
       阿霉素盐酸盐测定pH5.0      ·毫克/毫升           1.979           1.732   1.469  1.442  1.278乙酸盐     ·稳定性％            100.0           87.5    74.2   72.8   64.6
        pH                   5.04            5.06    5.04   5.05   5.05
       阿霉素盐酸盐测定pH5.5      ·毫克/毫升           2.023           1.847   1.548  1.330乙酸盐     ·稳定性％            100.0           91.3    76.5   65.7
       pH                    5.58            5.56    5.55   5.53
表4-2毫克/毫升阿霉素盐酸盐在无菌水中的溶液在各种pH下，在55℃下降解的Kobs
  值(1/日)
缓冲液           pH             Kobs×103 95％置信限
·甘氨酸-盐酸    2.0              309.5        ±12.7
(I＝0.05)
·甘氨酸-盐酸    2.5              138.3        ±0.6
(I＝0.05)
·甘氨酸-盐酸    3.0              93.1         ±4.6
(I＝0.05)
·甲酸盐         3.5              96.7         ±4.4
(I＝0.05)
·乙酸盐         4.0              269.8        ±18.7
(I＝0.05)
·乙酸盐         5.0              322.6        ±19.2
(I＝0.05)
·乙酸盐         5.5              415.4        ±45.7
(I＝0.05)
表5-2毫克/毫升阿霉素盐酸盐在5％葡萄糖中的溶液在各种pH下，在55℃
  下降解的Kobs值(1/日)
缓冲液              pH           Kobs×103      95％置信限
·甘氨酸-盐酸       2.0           323.8              ±17.2
  (I＝0.05)
·甘氨酸-盐酸       2.5           138.7              ±9.9
  (I＝0.05)
·甘氨酸-盐酸       3.0           100.5              ±5.9
  (I＝0.05)
·甲酸盐            3.5           132.0              ±20.7
  (I＝0.05)
·乙酸盐            4.0           209.7              ±12.7
  (I＝0.05)
·乙酸盐            5.0           273.1              ±27.7
  (I＝0.05)
·乙酸盐            5.5           453.7              ±59.2
  (I＝0.05)表6-2毫克/毫升阿霉素盐酸盐在0.9％盐水中的溶液，在各种pH下，在
  55℃降解的Kobs值(1/日)缓冲液                pH            Kobs×103      95％置信限·甘氨酸-盐酸         2.0              362.4           ±19.4(I＝0.05)·甘氨酸-盐酸         2.5              276.5           ±30.2(I＝0.05)·甘氨酸-盐酸         3.0              133.2           ±8.0(I＝0.05)·甲酸盐              3.5              148.1           ±11.1(I＝0.05)·乙酸盐              4.0              215.7           ±35.4(I＝0.05)·乙酸盐              5.0              301.2           ±60.1(I＝0.05)·乙酸盐              5.5              430.3           ±59.9(I＝0.05)例2.2毫克/毫升阿霉素盐酸盐在无菌水中的溶液中调至pH3.0
的贮存期限(t90％)的预测
阿霉素盐酸盐溶在注射用水中配成2毫克/毫升浓度，以0.5N盐酸调PH至3.0。此溶液在氮气压下通过0.22微米的微孔薄膜过滤。每份5.0毫升的试样在最高容量8毫升1型玻璃的玻璃小瓶中分别贮存于：
(a)55℃下21天；
(b)45℃和35℃下28天；
(c)27℃下90天。玻璃瓶用聚四氟乙烯涂面的氯丁胶塞和铝盖密封。在预定的时间测定小瓶中pH和阿霉素盐酸盐，其结果列入表7。
将各组结果的残余阿霉素盐酸盐浓度的对数对时间作图。发现呈线性关系，表明药物的降解在恒定pH和温度的情况下呈假—一级动力学关系。将观察的降解速度常数(Kobs)以残余的阿霉素盐酸盐浓度的自然对数对时间作图进行线性回归分析再次进行计算，如前述方程所示：
ln|DX|t＝ln|DX|o-Kobs·t
降解过程的Arrhenius方程式是从在不同温度下的试验(表8)得到的Kobs计算的。应用此方程式可计算出假—一级反应在4℃、8℃、15℃和27℃下的速度常数，以及在这些温度下的预期贮存期(t90％)。表8的t90％预测表明，2毫克/毫升的阿霉素盐酸盐的pH3.0的水溶液，如果贮存在冰箱中2°-8℃，可以达到有意义的贮存时间。表7-2毫克/毫升阿霉素盐酸盐在无菌水中的pH3的溶液在不同的时间和温度下
    的加速稳定性数据
                                                    时    间      (日)贮存温度    试  验              0          4           8     14       21        28       60      90
       阿霉素盐酸盐测定27℃       ·毫克/毫升         1.992                 1.993   1.988    1.962    1.94    1.908    1.850
       ·％稳定性          100.0                 100.1   99.8     98.5     97.4    95.8     92.9
        PH                 3.00                  2.95    2.94     2.95     2.94    2.96     2.93
       阿霉素盐酸盐测定35℃       ·毫克/毫升         1.992     1.985       1.952   1.889    1.876    1.808
       ·％稳定性          100.0     99.6        98.0    94.8     94.2     90.8
       pH                  3.00      2.96        2.98    2.93     2.92     2.92
       阿霉素盐酸盐测定45℃       ·毫克/毫升         1.992     1.919       1.851   1.677    1.565    1.393
       ·％稳定性          100.0     96.3        92.9    84.2     78.6     69.9
       pH                  3.00      2.97        2.95    2.85     2.92     2.90
       阿霉素盐酸盐测定55℃      ·毫克/毫升          1.992     1.760       1.493   1.036    0.730
      ·％稳定性           100.0     88.4        74.9    52.0     36.6
       pH                  3.00      2.94        2.90    2.80     2.82表8-Arrhenius法，假—一级速度常数
Arrhenius方程式，计算的t90％·假—一级速度常数，观测值(Kobs)
温度               kobs×103(1/日)             校正因数
27℃                   0.850                       0.986
35℃                   3.506                       0.983
45℃                   12.790                      0.995
55℃                   49.340                      0.995·27℃、35℃、45℃和55℃下速度常数的Arrhenius方程式 ln K obs = - 14083 T + 39.95 校正因数＝0.9988·假—一级速度常数，计算值(K)温度         K×103(1/-日)     +90％(日)         95％置信限4℃             0.019             5,652           3,079-10,3808℃             0.038             2,745           1,603-4,69715℃            0.130             810             532-1,23827℃            0.918             115             89-147例3.pH2.5-3.5的阿霉素制剂的长期稳定性
试验批号、试验制剂和所用包装均列入表9-11和18-20。制剂制备如下：
阿霉素盐酸盐溶于约9％标示量的注射水或生理盐水中，通氮气发泡驱除空气，滴加盐酸调溶液pH如表9和表18所报的数值。加入已通氮发泡驱除了空气的注射用水或生理盐水，以得到2毫克/毫升浓度的阿霉素盐酸盐溶液。在氮气压下溶液通过0.22μm微孔薄膜过滤。将此溶液分别取5毫升、10毫升和25毫升装入最高容量为8或10毫升、14毫升和39毫升的I型，无色的玻璃小瓶中。小瓶然后盖上聚四氟乙烯涂面的氯丁胶塞，并以铝帽密封。对制剂进行外观、澄明度、pH、无菌(8℃，每年)、阿霉素盐酸盐测定的试验。试验方法
外观和澄明度：肉眼检查
pH：美国药典XXI版。
无菌：美国药典(膜过滤)
阿霉素盐酸盐测定：高效液相色谱离子对法和美国药典高效液相
       色谱法(USPXXI)
高效液相色谱离子对法测定阿霉素盐酸盐法简介：
柱的填充：反相.zorbax TMS
移动相：水∶乙腈∶甲醇(54∶29∶17V/V/V)含2毫升/升
        85％磷酸和1毫克/毫升十二烷基硫酸钠〔离子对试剂
        (Pairing agent)〕，以2N氢氧化钠调pH3.5。
移动相流速：1.5毫升/分。
柱温：室温(22°±2℃)
分析波长：254nm
系统适宜参数：对称因数0.7-1.2之间；
              理论塔板数≥2500；
              测定重现性：变动因数＜1，n＝6；
              分辨因数≥12
高效液相色谱离子对法测定阿霉素盐酸盐的准确度，精密度，线性，灵敏度、专一性和稳定性指示已经确认。
对阿霉素盐酸盐的百分稳定性(离子对法)和pH测定的结果(对
直立存放的小瓶)列于：
表12存于-20℃
表13和21存于+4℃
表14和22存于+8℃
表15和23存于+15℃
表16和24存于+27℃
表17存于100和250呎烛光。
表25存于250呎烛光。
这些表中的阿霉素盐酸盐的测定是三次分别测定的平均值。各种助剂的稳定作用也列入表26。
在稳定试验中所检测到的其他参数：
-在所有的贮存条件下所检查的所有溶液的澄清度无变化。
-溶液的外观：
a)4℃和8℃下贮存的所有的样品经检测都无变化；
b)在15℃贮存的9个月后略变暗；
在27℃贮存的3个月后略变暗；
在100和250呎烛光贮存的3个月后略变暗。
-所有贮存条件下进行的所有的检查，密闭系统没有变化。
-在8℃下贮存12个月后仍保持无菌。
倒立存放的小瓶的对照结果与直立存放的小瓶的结果相比没有显著差别。
用美国药典高效液相色谱法测得的阿霉素盐酸盐百分稳定性值与表12-17中列出的用高效液相色谱离子对法测得的数值相比没有显著差别。
所得的稳定性数据表明，具有不同pH值(范围2.5-3.5)的测试的阿霉素盐酸盐溶液达到仍可被使用的低限(90％标示浓度)的存放条件是：在15℃下约9个月，在27℃下约2-3个月。但在4℃和8℃下证明可以稳定到12个月，而4℃，8℃是在电冰箱内贮存产品的通常温度。这一点与由市售的冻干制剂经重新配制得到的阿霉素盐酸盐溶液成鲜明的对比，后者的pH在4.5-6变化，并显示其稳定性低得多。实际上，建议重新配制的溶液在电冰箱中仅存放48小时后就应该弃掉。
              表9-稳定性研究，批试验
批    批号特征   TF/23049  TF/23077   TF/23078   TF/23117   TF/23119     H0001   L0001   M0001
阿霉素盐酸盐每只小瓶 10 10 10 20 50 10 20 50
 pH     3.06     2.81     3.50     2.97     3.08     3.15     3.05     3.20
制剂号 FI6804/IL1   FI6804/IL1  FI6804/IL1  FI6804/IL2  FI6804/IL3  FI6804/IL4 FI6804/IL5  FI6804/IL6
批规模小瓶数     700     400     400     500     500     2,400     2,300     2,400
表10-稳定性研究，制剂试验
                                                制剂编号每只瓶的成份
             F16804/IL1       FI6804/IL2      F16804/IL3     F16804/IL4      F16804/IL5     F16804/IL6阿霉素盐酸盐         10               20               50          10                20             50毫克盐酸              2.8-3.5          2.8-3.5          2.8-3.5      2.8-3.5           2.8-3.5       2.8-3.5适量至pH水，适量至毫升      5.0              10.0             25.0         5.0              10.0           25.0表11-稳定性研究，所用包装
Figure C8710822500281
表12-2毫克/毫升阿霉素盐酸盐溶液，在-20℃的稳定性数据，
     (小瓶直立存放)收集数据3个月
                                           时间-月数批剂量
                              0             1           3H0001
      阿霉素盐酸盐           100          99.9          99.610毫克    ％稳定性
      pH                     3.15         3.12          2.98L0001     阿霉素盐酸盐           100          100.8         99.820毫克    ％稳定性
      pH                     3.05         2.84          2.97M0001     阿霉素盐酸盐           100          100.7         101.050毫克    ％稳定性
      pH                     3.20         2.96          2.99表13--2毫克/毫升阿霉素盐酸盐溶液
  4℃下的稳定性数据(小瓶直立贮存)，收集到24个月批        时间           0      1      3      6      9      12      18      24剂量      月数TF/23049    *           100   99.9  100.6   98.3   98.2     97.7    96.9   97.110毫克      **          3.06  3.09  3.10    3.10   3.05     2.97    3.07   3.00TF/23077    *           100   101.7 99.3    97.9   98.0     99.8    96.410毫克      **          2.81  2.86  2.75    2.65   2.67     2.76    2.70TF/23078    *           100   101.2 98.8    97.8   98.8     96.8    96.310毫克      **          3.50  3.54  3.49    3.44   3.43     3.54    3.50TF/23117    *           100   96.8  96.6    98.1   98.8     97.5    98.720毫克      **          2.97  2.98  2.92    2.86   2.95     2.98    3.00TF/23119    *           100   98.6  99.1    98.9   98.4     97.5    98.850毫克      **          3.08  2.98  2.98    2.89   2.99     3.00    3.00H0001       *           100         97.6    99.2   99.6     100.4   98.610毫克      **          3.15  n.d.  3.06    3.22   3.20     3.10    3.20L0001       *           100         98.8    98.4   99.2     99.4    99.920毫克      **          3.05  n.d.  2.99    2.94   3.00     2.90    3.00M0001       *           100         99.7    99.7   100.3    100.6   100.450毫克      **          3.20  n.d.  3.00    3.04   3.10     3.00    3.10*阿霉素盐酸盐稳定性％**pHn.d.＝未测定表14--2毫克/毫升阿霉素盐酸盐溶液8℃下稳定性数据(小瓶直立贮存)，收集到24个月批           时间         0       1         2         3        6        9      12        18      24剂量         月数TF/23049      *          100     99.7                100.1    96.5     96.1    96.5    95.4      91.110毫克        **         3.06    3.07                3.09     3.07     3.04    2.96    3.04      3.0TF/23077      *          100     102.1               101.6    97.5     96.6    95.0    94.710毫克        **         2.81    2.81                2.74     2.65     2.67    2.75    2.70TF/23078      *          100     98.3                97.7     96.5     95.9    98.8    92.810毫克        **         3.50    3.59                3.47     3.27     3.43    3.51    3.40TF/23117      *          100     95.7                95.8     97.8     96.2    95.5    95.920毫克        **         2.97    2.97                2.92     2.85     2.96    2.98    3.00TF/23119      *          100     97.6                97.8     96.2     97.3    96.8    97.250毫克        **         3.08    2.94                2.94     2.87     2.99    3.00    3.00H0001         *          100     98.2      99.4      96.4     96.7     98.0    98.9    96.710毫克        **         3.15    3.12      3.16      3.05     3.23     3.20    3.10    3.20L0001         *          100     100.6     99.1      98.1     98.3     98.1    99.5    99.720毫克        **         3.05    2.84      2.83      2.97     2.94     3.00    2.90    3.00M0001         *          100     100.3     100.6     98.7     99.0     98.4    99.1    97.750毫克        **         3.20    2.96      2.97      3.01     3.03     3.10    3.00    3.10*阿霉素盐酸盐的稳定性％**pH表15--2毫克/毫升阿霉素盐酸盐溶液
15℃下稳定性数据(小瓶直立贮存)收集到12个月批           时间          0         0.5           1        2       3       6       9       12剂量         月数TF/23049       *         100         97.8         98.9             97.1    92.7    92.9     90.210毫克         **       3.06         3.03         3.07             3.10    3.08    3.02     2.95TF/23077       *         100        100.4        101.9             98.8    94.6    92.7     91.110毫克         **       2.81         2.81         2.85             2.71    2.63    2.67     2.74TF/23078       *         100        101.4         98.4             95.3    94.6    91.9     90.710毫克         **       3.50         3.51         3.58             3.47    3.38    3.41     3.47TF/23117       *         100         99.1         96.4             95.2    94.6    90.7     88.020毫克         **       2.97         2.95         2.95             2.90    2.81    2.95     3.00TF/23119       *         100         97.4         97.1             95.9    92.7    90.6     87.450毫克         **       3.08         2.99         2.95             2.91    2.87    2.98     3.00H0001          *         100                      97.9   97.1      94.8    94.6    95.5     91.810毫克         **       3.15                      3.12   3.16      3.06    3.23    3.10     3.00L0001.         *         100                     100.5   98.7      95.3    95.5    96.3     93.220毫克         **       3.05                      2.85   2.87      2.98    2.96    3.00     3.00M0001          *         100                      99.4  100.3      97.2    95.6    95.6     93.750毫克         **       3.20                      2.96   2.94      3.01    3.04    3.00     3.00*阿霉素盐酸盐稳定性％**pH表16--2毫克/毫升阿霉素盐酸盐溶液
  在27℃下稳定性数据(小瓶直立贮存)收集到6个月批               时间          0         0.5     1        2       3          6剂量月数TF/23049          *            100      97.2    95.8             87.9      73.610毫克           **           3.06      2.98    3.07             3.08      3.03TF/23077          *            100      98.5    96.2             86.4      69.210毫克           **           2.81      2.80    2.85             2.71      2.64TF/23078          *            100     101.2    94.5             80.5      71.110毫克           **           3.50      3.51    3.58             3.38      3.13TF/23117          *            100      97.4    93.2             81.9      66.620毫克           **           2.97      2.95    2.94             2.88      2.77TF/23119          *            100      96.0    93.3             85.3      66.850毫克           **           3.08      2.97    2.97             2.91      2.82H0001             *            100              94.5       94.2  86.610毫克           **           3.15              3.10       3.09  3.01L0001             *            100              97.2       94.3  89.320毫克           **           3.05              2.84       2.85  2.96M0001             *            100              96.5       93.6  88.150毫克           **           3.20              2.95       2.95  2.99*阿霉素盐酸盐稳定性％**pH表17--2毫克/毫升阿霉素盐酸盐溶液，在100和250呎烛光下的
稳定性(小瓶倒立存放)，收集到3个月批              时间            100呎烛光                                250呎烛光剂量            月数         0      0.5          1         3         0.5         1       2       3TF/23049         *          100    96.3        95.9       81.3       95.9       94.810毫克          **         3.06    3.05        3.05       3.06       2.99       3.04TF/23077         *          100    98.3        98.1       87.7       97.3       94.510毫克          **         2.81    2.79        2.84       2.70       2.79       2.84TF/23078         *          100    99.6        96.4       88.0       97.8       89.710毫克          **         3.50    3.50        3.58       3.39       3.47       3.53TF/23117         *          100    96.8        96.7       91.7       98.1       94.620毫克          **         2.97    2.93        2.95       2.87       2.95       2.93TF/23119         *          100    96.9        96.7       89.6       96.4       95.050毫克          **         3.08    2.96        2.95       2.93       2.96       2.97H0001            *          100                                                 95.2     93.7    87.810毫克          **         3.15                                                 3.10     3.06    2.97L0001            *          100                                                 96.5     93.0    86.520毫克          **         3.05                                                 2.84     2.85    2.97M0001            *          100                                                 97.8     91.5    85.350毫克          **         3.20                                                 2.95     2.94    2.99*阿霉素盐酸盐稳定性**pH表18-稳定性研究，批试验批                                      批  号特点                     P0001             Q0001          R0001阿霉素盐酸盐
                     10                20             50每瓶(毫克)pH                       3.00              3.00           3.00制剂号                   F16804/IL7        FI6804/IL8     FI6804/IL9批规模                   2,400             2,200          2,500小瓶数表19-稳定性研究，制剂试验
                            制剂编号每瓶的成分         F16804/IL7    F16804/IL8    F16804/IL9阿霉素盐酸盐           10            20            50毫克盐酸                   2.8-3.5       2.8-3.5       2.8-3.5适量至pH0.9％氯化钠            5.0           10.0          25.0注射液适量至毫升表20-稳定性研究，所用包装
                                批  号包装                      P0001          Q0001            R0001小瓶玻璃类型                I              I               I小瓶最高容积             10毫升          14毫升          39毫升
                    氯丁烯胶塞     氯丁烯胶塞      氯丁烯胶塞胶塞
                  聚四氟乙烯涂面  聚四氟乙烯涂面  聚四氟乙烯涂面铝盖                       铝              铝              铝表21-2毫克/毫升pH＝3的阿霉素盐酸盐在生理盐水中的注射溶液，
在4℃的稳定数据(小瓶直立存放)，收集到12和18个月。批                                             时间—月数剂量                    0            3          6         9         12      18
   阿霉素盐酸盐P0001  的稳定性％      100          98.3       98.0    99.2        97.910毫克 pH              3.00         2.93       2.98    2.90        2.90
   阿霉素盐酸盐Q0001  的稳定性％      100          97.5       97.0    100.1       98.920毫克 pH              3.01         3.06       3.03    3.00        3.00
   阿霉素盐酸盐R0001  的稳定性％      100          99.8       100.7   101.2       101.7   100.950毫克 pH              3.02         3.08       3.15    3.14        3.10    3.10表22-2毫克/毫升的pH＝3的阿霉素盐酸盐在生理盐水中的注射用溶液，
在8℃的稳定性数据(小瓶直立存放)，收集到12和18个月。批                                     时间-月数剂量                      0      1      2       3       6       9       12      18
   阿霉素盐酸盐P0001  稳定性％          100   101.0   100.6   97.9    97.4    96.8    96.110毫克 pH                3.00  2.93    2.89    2.91    3.00    2.90    3.00
   阿霉素盐酸盐Q0001  稳定性％          100   99.4    99.9    96.8    96.7    95.7    96.020毫克 pH                3.01  3.02    3.01    3.05    3.02    3.00    3.00
   阿霉素盐酸盐R0001  稳定性％          100   99.8    99.8    98.4    98.5    99.5    100.9   99.750毫克 pH                3.02  3.02    3.09    3.08    3.13    3.13    3.10    3.10表23-2毫克/毫升的pH＝3的阿霉素盐酸盐在生理盐水中的注射用溶液，在
15℃的稳定性数据(小瓶直立贮存)收集到12个月批                                              时间—月数剂量
                           0         1        2       3      6      9      12
      阿霉素盐酸盐P0001     稳定性％           100       100.6      99.9   95.9   94.0   89.1    89.710毫克    pH                 3.00      2.93       2.89   2.90   2.99   2.90    2.90
      阿霉素盐酸盐Q0001     稳定性％           100       98.6       97.8   95.1   96.4   89.8    88.320毫克    pH                 3.01      3.01       3.01   3.04   3.01   3.00    3.00
      阿霉素盐酸盐R0001     稳定性％           100       98.8       97.5   97.6   94.7   96.0    94.550毫克    pH                 3.02      3.02       3.08   3.08   3.14   3.11    3.10表24-2毫克/毫升pH＝3的阿霉素盐酸盐在生理盐水的
注射用溶液，在27℃的稳定性数据(小瓶直立贮
存)，收集到3个月。批                                      时间—月数剂量                          0          1          2             3
    阿霉素盐酸盐P0001   稳定性％             100        98.3       95.0          84.910毫克  pH                   3.00       2.33       2.89          2.88
    阿霉素盐酸盐Q0001   稳定性％             100        96.0       93.2          83.820毫克  pH                   3.01       3.01       2.99          3.03
    阿霉素盐酸盐R0001   稳定性％             100        95.6       92.2          88.750毫克  pH                   3.02       3.02       3.06          3.05表25-2毫克/毫升的pH＝3的阿霉素盐酸盐在生理盐水
中的注射用溶液，在室温和250呎烛光下的稳定
性数据，(小瓶直立贮存)，收集到3个月。批                                            时间-月数剂量                         0             1          2             3
    阿霉素盐酸盐P0001   的稳定性％          100          89.6        86.5         70.310毫克  pH                  3.00         2.92        2.86         2.84
    阿霉素盐酸盐Q0001   的稳定性％          100          91.1        84.5         72.720毫克  pH                  3.01         2.99        2.97         2.98
    阿霉素盐酸盐R0001   的稳定性％          100          96.0        91.4         86.650毫克  pH                  3.02         3.01        3.04         3.02各种辅助剂的稳定作用表26-2毫克/毫升pH 3.0的阿霉素溶液在45℃的稳定数据
                                   ％最初稳定剂及其浓度                1Wk       2Wk           4Wk          8Wk水                            87.8      75.9          53.8        25.55％葡萄糖                     91.1      82.3          65.6        38.85％半乳糖                     91.5      86.1          64.3        --5％果糖                       91.9      80.6          64.1        --4％α-L(-)-岩藻糖             91.2      81.9          63.8        --4％α-D(+)岩藻糖              91.8      81.9          63.3        --1％乳糖                       91.3      81.7          64.5        34.84％葡萄糖，MW9,000            90.5      81.5          --          --4％葡萄糖，MW506,000          92.0      84.0          --          --4％α-环糊精                  91.7      84.3          --          --4％β-环糊精                  92.1      84.1          --          --4％γ-环糊精                  94.3      89.0          --          --5％甘露糖醇                   90.7      81.4          65.8        41.15％山梨糖醇                   91.4      83.0          67.2        42.50.5％硫代甘油                 90.8      83.2          63.5        --5％肌醇                       91.7      84.9          --          --5％乙醇                       92.2      85.6          --          --10％甘油                      92.2      83.4          65.5        --注意：上述辅助剂在低浓度下也可能有同样的稳定作用，如降低值
   至多为25-50wt％。例4.2毫克/毫升调至pH3.0和含有0.9％(重量)氯化钠的阿霉
素盐酸盐在无菌水中的溶液的贮存期限(t90％)的预测。
将阿霉素盐酸盐溶于生理盐水，浓度为2毫克/毫升，以0.5N盐酸调pH至3.0。此溶液在氮气压下通过0.22微米的微孔薄膜。每份5.0毫升的样品贮存在：
(a)60℃下4日；
(b)55℃下11日；
(c)45℃下21日；
(d)35℃下28日。样品贮存在1型玻璃的玻璃小瓶中，最大容积为8毫升，聚四氟乙烯涂表面的氯丁基胶塞、铝盖。在予定的时间分析阿霉素盐酸盐和pH，其结果列入表27。
将各组结果测得的残余阿霉素盐酸盐浓度的对数对时间作图。发现呈线性关系，表明药物的降解在恒定pH和温度的情况下遵照假-一级动力学。将观察的降解速度常数(Kobs)以残余阿霉素盐酸盐浓度的自然对数对时间的图进行线性回归分析再次计算，如前述方程所示：
ln|DX|t＝ln|DX|o-Kobs·t
降解过程的Arrhenius方程式是以在不同温度下的试验(表28)的Kobs计算出来的。应用此方程式可计算出假—一级反应在4℃、8℃、15℃和27℃下的速度常数，以及在这些温度下的预期的贮存界限(t90％)。表28的t90％预测表明，2毫克/毫升的阿霉素盐酸盐在pH3.0和在0.9％氯化钠的水溶液中，如果贮存在冰箱中(2℃至8℃)，可以达到有意义的贮存时间。表27-2毫克/毫升阿霉素盐酸盐在0.9％氯化钠中，在不同时间和温度下的加速稳定性数据贮存                                                   时    间    (日)条件           试验              0      1      2      3      4      8      11      14      21      28
       阿霉素盐酸盐测定35℃      ·毫克/毫升          2.061                              2.045          1.946    1.932   1.852
      ·％稳定性           100.0                              99.2           94.4     93.7    89.9
      PH                   3.05                               2.98           2.92     2.92    2.98
      阿霉素盐酸盐45℃      ·毫克/毫升          2.061                        1.996 1.724         1.517     1.344
      ·％稳定性           100.0                        96.5  83.6          73.6      65.2
      PH                   3.05                         2.98  2.97          2.98      2.93
      阿霉素盐酸盐55℃      ·毫克/毫升          2.061                        1.450 1.066   0.900
      ·％稳定性           100.0                        70.4  51.7    43.7
      PH                   3.05                         2.90  2.97    2.95
      阿霉素盐酸盐60℃      ·毫克/毫升          2.061  1.742  1.481  1.290   1.050
      ·％稳定性           100.0  84.5   71.9   62.6    50.9
      PH                   3.05   2.97   2.96   2.98    2.96表28-2毫克/毫升阿霉素盐酸盐的在0.9％氯化钠中的pH3.0的
   溶液
   Arrhenius法。假—一级速度常数
   Arrhenius方程式。计算的t90％
   假—一级速度常数，观测值(Kobs)温度                   Kobs×103(1/日)           校正因数35℃                     3.89                        0.96545℃                     21.61                       0.98755℃                     75.90                       0.99660℃                     164.9                       0.99835℃、45℃、55℃和60℃速度常数的Arrhenius方程式 ln K obs = - 15100 T + 43.53 校正因数＝0.9986假—一级速度常数，计算值(K)温度              K×103(1/日)      t90％(日)          95％置信限4℃                 0.017             6,166             (1,670-22,756)8℃                 0.037             2,838             (861-9,351)15℃                0.137             768               (281-2,105)27℃                1.112             94                (45-197)例5.2毫克/毫升阿霉素盐酸盐在无菌水中的调至pH3和含5％
(重量)葡萄糖的溶液的贮存期限(t90％)预测
阿霉素盐酸盐溶于含5％(重量)葡萄糖的注射用水中，浓度2毫克/毫升。以0.5N盐酸调pH至3.0。溶液在氮气压下通过0.22微米的微孔薄膜过滤。每份体积为5.0毫升样液贮存在：
(a)60℃8日；
(b)55℃28日；
(c)45℃28日；
(d)35℃28日。样液存在I型玻璃的玻璃小瓶中，小瓶的最大容积为8毫升，聚四氟乙烯涂面的氯丁基胶塞，铝盖。在预定的时间分析小瓶的阿霉素盐酸盐和pH，结果列入表29。
将各组结果的残余阿霉素盐酸盐浓度对数对时间作图，发现呈线性关系，表明药物的降解在恒定pH和温度的情况下呈假—一级动力学。将观察的降解速度常数(Kobs)以残余阿霉素盐酸盐浓度的自然对数对时间作图进行线性回归分析重新计算，如前述方程式所示：
ln|DX|t＝ln|DX|o-Kobs·t
降解过程的Arrhenius方程式是以在不同温度下的试验的(表30)Kobs计算的。应用此方程式可计算出假—一级反应在4℃、8℃、15℃和27℃下的速度常数，以及在这些温度下的预期的贮存期。表30的t90％预测表明，2毫克/毫升的阿霉素盐酸盐的pH3.0的在5％葡萄糖中的水溶液，如贮存在冰箱中(2℃至8℃)，可以达到有意义的贮存时间。表29-2毫克/毫升阿霉素盐酸盐的pH3.0的在5％葡萄糖中的溶液，在不同的时间和温度
   下的加速稳定性数据贮存                                            时        间        (日)条件    试验                 0        2      4        6       8       11      14     17     21      28
    阿霉素盐酸盐测定35℃    ·毫克/毫升         2.114          2.044            2.034           2.015         1.934    1.859
    ·稳定性％          100.0          96.7             96.2            53.3          91.5     87.9
    PH                  3.02           2.98             2.94            2.95          2.90     2.94
    阿霉素盐酸盐45℃    ·毫克/毫升         2.114          1.940            1.870           1.684         1.510    1.410
    ·稳定性％          100.0          91.8             88.5            79.7          71.5     66.7
    PH                  3.02           2.97             2.98            2.95          2.96     2.96
    阿霉素盐酸盐55℃    ·毫克/毫升         2.114          1.718            1.415           1.112         0.957    0.796
    ·稳定性％          100.0          81.3             66.9            52.6          45.3     37.7
    PH                  3.02           2.95             2.92            2.99          2.91     2.95
    阿霉素盐酸盐60℃    ·毫克/毫升         2.114  1.752   1.393   1.176    0.925
    ·稳定性％          100.0  82.9    65.9    55.7     43.8
     PH                 3.02   2.96    2.98    2.96     2.97表30-2毫克/毫升阿霉素盐酸盐的pH3.0的在5％葡萄糖中的溶
    液
    Arrhenius法，假—一级速度常数
    Arrhenius方程式计算的t90％
    假—一级速度常数，观测值(Kobs)
       温度          Kobs×103(1/日)    校正因数
       35℃               4.190            0.990
       45℃               14.55            0.995
       55℃               58.11            0.998
       60℃               102.6            0.999
       ·35℃、45℃、55℃和60℃速度常数的Arrhenius方程 ln K obs = - 13266 T + 37.56
       校正因数＝0.9993
       假—一级速度常数，计算值(K)
       温度             K×1103(1/日)        t90％(日)          95％置信限
        4℃             0.0326                 3,218            (1,463-7,082)
        8℃             0.0645                 1.628            (792-3,344)
        15℃            0.203                  516              (281-949)
        27℃            1.283                  82               (53-128)例6.阿霉素盐酸盐溶液在pH3.7的长期稳定性制备阿霉素盐酸盐(2毫克/毫升)的含0.9％(重量)氯化钠的无菌水溶液(TF/23256批，10毫克)。以0.1N盐酸调pH至3.7。在不同贮存温度下的溶液稳定数据列入下表31表31
                                       时间(月数)贮存温度  试验                        0          1            3
      阿霉素盐酸盐测定8℃       (毫克/毫升)               2.064      2.054       2.063
      稳定性％                  100.0      99.3        100.0
      PH                        3.7        3.7         3.6
      阿霉素盐酸盐15℃      (毫克/毫升)               2.064      2.073       2.029
      稳定性％                  100.0      100.5       98.4
      PH                        3.7        3.7         3.6
      阿霉素盐酸盐27℃      (毫克/毫升)               2.064      1.888       1.545
      稳定性％                  100.0      91.5        74.9
      PH                        3.7        3.6         3.3
例7.4′-表阿霉素溶液的稳定性
如前制备相应的阿霉素溶液的同样方法制备表阿霉素的溶液。也用同样的方法试验其稳定性。结果列入表32至61，并在图4至6中说明。表32-2毫克/毫升表阿霉素盐酸盐在无菌水中的溶液在各种
 pH下的加速(55℃)稳定性数据
                                              时            间  (小时)缓冲液        试验              0          16        24      48      72      96     120pH2.0表阿霉素盐酸盐的测定甘氨酸·毫克/毫升              2.007    1.874      1.801    1.725   1.697    1.478  1.330-盐酸 ·初值的％               100.0    93.4       89.7     85.9    83.7     73.7   46.3
   PH                      2.0      2.0        2.0      2.0     2.0      2.0    2.0pH2.5表阿霉素盐酸盐的测定甘氨酸·毫克/毫升              2.033    1.972      1.923    1.823   1.777    1.622  1.572-盐酸 ·初值的％               100.0    99.9       94.6     89.7    87.4     79.8   77.3
   PH                      2.5      2.4        2.5      2.5     2.4      2.4    2.4pH3.0表阿霉素盐酸盐的测定甘氨酸·毫克/毫升              2.055    2.008      1.917    1.764   1.709    1.571  1.494-盐酸 ·初值的％               100.0    97.7       93.3     85.8    83.2     76.4   72.7
   pH                      2.9      2.9        2.9      2.8     2.9      2.9    2.9pH3.5表阿霉素盐酸盐的测定甲酸盐·毫克/毫升              2.047    1.829      1.764    1.604   1.505    1.192  1.101
  ·初值的％               100.0    89.4       86.2     78.3    73.5     58.2   53.8
   PH                      3.4      3.4        3.4      3.4     3.3      3.3    3.3pH4.0表阿霉素盐酸盐的测定乙酸盐·毫克/毫升              2.011    1.848      1.442    1.301   0.964           0.573
  ·初值的％               100.0    91.9       71.7     64.7    47.9     n.d.   28.5
   PH                      4.0      4.0        4.0      4.0     4.0             3.9表阿霉素盐酸盐的测定pH 5.0·毫克/毫升              2.064    1.868      1.541    1.263   0.896乙酸盐·初值的％               100.0    90.5       74.6     61.2    43.4     n.d.   n.d.
   PH                      5.0      5.0        5.0      5.0     5.0表阿霉素盐酸盐的测定pH5.5 ·毫克/毫升              2.056    1.794      1.426乙酸盐·初值的％               100.0    87.3       69.4     n.d.    n.d.     n.d.   n.d.
   PH                      5.5      5.5        5.4n.d.＝未测定表33-2毫克/毫升表阿霉素盐酸盐在0.9％氯化钠注射液中的溶液，在各种pH下加速(55℃)稳定性数据
                                                     时            间        (小时)缓冲液           试  验              0       4        8       16      24      34      48      72     96     120     144
         表阿霉素盐酸盐测定pH 1.5      ·毫克/毫升             2.085                   1.675   1.372   1.246   1.062盐酸-氯化钾 ·初始值的％            100.0   n.d.     n.d.   80.3    65.8    59.8    50.9     n.d.   n.d.    n.d.    n.d.
         pH                     1.6                     1.5     1.5     1.6     1.6
        表阿霉素盐酸盐测定pH 2.0      ·毫克/毫升             2.077            2.065  1.994   1.940   1.657   1.587    1.282  1.121   0.928甘氨酸-盐酸 ·初始值的％            100.0   n.d      99.4   96.0    93.0    79.8    76.4     61.8   54.0    44.7    n.d.
         pH                     2.0              2.0    1.9     1.9     2.0     2.0      2.0    2.0     1.9
        表阿霉素盐酸盐测定pH 2.5      ·毫克/毫升             2.077            2.066  1.987                   1.781    1.665  1.449   1.285   1.175甘氨酸-盐酸 ·初始值的％            100.0   n.d.     99.5   95.7    n.d.    n.d.    85.7     80.2   69.8    61.9    56.6
         pH                     2.4              2.4    2.4                     2.4      2.4    2.4     2.4     2.4
        表阿霉素盐酸盐测定pH 3.0      ·毫克/毫升             2.058                   1.951   1.934   1.869   1.784    1.668  1.483   1.349   1.253甘氨酸-盐酸 ·初始值的％            100.0   n.d.     n.d.   94.8    94.0    90.8    86.7     81.0   72.1    65.5    60.9
                                3.0                     2.9     2.9     2.9     2.9      2.9    2.9     2.9     2.9n.d.＝未测定表33-2毫克/毫升表阿霉素盐酸盐在0.9％氯化钠注射液中的溶液，在各种pH下加速
  (55℃)稳定性数据(续)
                                                      时    间      (小时)缓冲液          试  验            0      4      8      16      24      34     48      72      96       120       144
        表阿霉素盐酸盐测定pH 3.5      ·毫克/毫升          2.047                1.891           1.711  1.662  1.360   1.265甲酸盐      ·初始值％           100.0 n.d.   n.d.    92.4     n.d.   83.6   81.2   70.5    61.8       n.d.      n.d.
        pH                   3.3                  3.2             3.3    3.3    3.2     3.2
        表阿霉素盐酸盐测定pH 4.0     ·毫克/毫升           2.088 2.073          1.892           1.699  1.606  1.454乙酸盐     ·初始值％            100.0 99.3   n.d.    90.6     n.d.   81.3   76.9   69.4    n.d.       n.d.      n.d.
        pH                   4.0   3.9            3.9             3.9    3.9    3.9
       表阿霉素盐酸盐测定pH 5.0     ·毫克/毫升           2.114 2.049  1.954   1.782    1.535乙酸盐     ·初始值％            100.0 97.0   92.4    84.3     72.6   n.d.   n.d.   n.d.    n.d.       n.d.      n.d.
        pH                   5.0   5.0    5.0     5.0      4.9n.d.＝未测定表34-2毫克/毫升表阿霉素盐酸盐在5％葡萄糖中的溶液，在不同pH下加速(55℃)稳定性数据
                                                       时            间  (小时)缓冲液           试  验             0       4       8       16       24     34      48       72     96      120      144pH1.5        表阿霉素盐酸盐测定盐酸-氯化钾  ·毫克/毫升            2.032         1.922   1.782    1.649   1.418            0.982   0.625
         ·初始值的％           100.0  n.d.   94.6    87.7     81.1    69.8     n.d.    48.3    30.7    n.d.     n.d.
         pH                     1.4           1.4     1.4      1.4     1.4              1.4     1.4pH2.0        表阿霉素盐酸盐测定甘氨酸-盐酸  ·毫克/毫升            2.033                 1.968    1.959   1.822    1.809   1.574   1.380   1.252    1.094
         ·初始值的％           100.0  n.d.   n.d.    96.8     96.4    89.6     89.0    77.4    67.9    61.6     53.8
         pH                     1.9                   1.9      1.9     1.9      1.9     1.9     1.9     1.9      1.9pH2.5        表阿霉素盐酸盐测定甘氨酸-盐酸  ·毫克/毫升            2.105                 1.921    1.909   1.815    1.819   1.624   1.521            1.264
         ·初始值的％           100.0  n.d.   n.d.    91.3     90.7    86.2     86.4    77.1    72.3    n.d.     60.0
          pH                    2.4                   2.3      2.3     2.3      2.3     2.3     2.3              2.3pH3.0        表阿霉素盐酸盐测定甘氨酸-盐酸  ·毫克/毫升            2.029         1.990   1.914    1.949   1.866    1.743           1.562   1.442    1.318
         ·初始值的％           100.0  n.d.   98.1    94.3     96.11   92.0     85.9    n.d.    77.0    71.1     65.0
          pH                    2.9           2.8     2.9      2.8     2.8      2.8             2.8     2.8      2.8n.d.＝未测定表34-2毫克/毫升表阿霉素盐酸盐在5％葡萄糖中的溶液，在不同pH下加速
(55℃)稳定性数据(续)
                                                  时        间          (小时)缓冲液        试  验            0       4       8      16      24         34        48       72        96        120       144
      表阿霉素盐酸盐测定pH3.5     ·毫克/毫升          2.024          1.949   1.938   1.851     1.807                1.613   1.356甲酸盐    ·初始值的％         100.0   n.d.   96.3    95.7    91.4      89.3        n.d.     79.7    67.0       n.d.       n.d.
       pH                  3.3            3.3     3.3     3.3       3.3                  3.3     3.2
      表阿霉素盐酸盐测定pH4.0     ·毫克/毫升          2.056  1.964   1.937           1.787                 1.501乙酸盐    ·初始值的％         100.0  95.5    94.2    n.d.    86.9      n.d.        73.0     n.d.    n.d.       n.d.       n.d.
      pH                   4.0    3.9     3.9             4.0                   4.0
      表阿霉素盐酸盐测定pH5.0     ·毫克/毫升          2.026  1.935   1.840   1.734   1.608     1.279乙酸盐    ·初始值的％         100.0  95.5    90.8    84.3    79.4      62.2        n.d.     n.d.    n.d.       n.d.       n.d.
       pH                  5.1    5.0     5.0     5.0     5.0       5.0n.d.＝未测定表35-2毫克/毫升表阿霉素盐酸盐在注射用水溶液中，在不同
 pH下，在55℃的降解的Kobs(1/日)缓冲液                      pH            Kobs×103        95％置信限·甘氨酸-盐酸(I＝0.05)                 2.0             79.0                 ±6.9·甘氨酸-盐酸(I＝0.05)                 2.5             55.1                 ±4.0·甘氨酸-盐酸(I＝0.05)                 3.0             66.8                 ±5.4·甲酸盐(I＝0.05)                 3.5             125.4                ±17.1·乙酸盐(I＝0.05)                 4.0             376.7                ±60.6·乙酸盐(I＝0.05)                 5.0             430.4                ±42.8表36-2毫克/毫升表阿霉素盐酸盐在0.9％氯化钠注射液中的
 溶液，在各种pH下，在55℃的降解的Kobs(1/日)缓冲液               pH          Kobs×103              95％置信限·盐酸-氯化钾(I＝0.05)            1.5            343.2                     ±51.1·甘氨酸-盐酸(I＝0.05)            2.0            168.9                     ±10.2·甘氨酸-盐酸(I＝0.05)            2.5            97.3                      ±6.4·甘氨酸-盐酸(I＝0.05)            3.0            84.8                      ±6.5·甲酸盐(I＝0.05)            3.5            124.5                     ±14.0·乙酸盐(I＝0.05)            4.0            124.8                     ±13.6·乙酸盐(I＝0.05)            5.0            318.1                     ±52.1表37-2毫克/毫升表阿霉素在5％葡萄糖溶液中的溶液在各种pH下，在55℃的降解的Kobs(1/日)缓冲液                        pH            Kobs×103           95％置信限·盐酸-氯化钾(I＝0.05)                     1.5            288.1                  ±23.1·甘氨酸-盐酸(I＝0.05)                     2.0            106.9                  ±7.7·甘氨酸-盐酸(I＝0.05)                     2.5            81.1                   ±6.6·甘氨酸-盐酸(I＝0.05)                     3.0            70.9                   ±4.8·甲酸盐(I＝0.05)                     3.5            89.1                   ±9.3·乙酸盐(I＝0.05)                     4.0            150.6                  ±17.0·乙酸盐(I＝0.05)                     5.0            225.7                  ±12.9表38-稳定性研究，在0.9％氯化钠注射液中的批试验
        批号                  TF/23274       TF/23275           6001LA批特点每瓶表阿霉素盐酸盐(毫克)
                                10              10                10PH                                  2.9             3.5               3.0制剂号                              FI7701/IL2      FI7701/IL2        FI7701/IL2批量小瓶数                              584             586               595制造规模*                          Lab             Lab               S-i阿霉素盐酸盐批号                    6016G669        6016G669          6016G669
         批号                   6001LB          6001LC批特点每瓶表阿霉素盐酸盐(毫克)                          20              50PH                                  3.1             2.7制剂号                              FI7701/IL3      FI7701/IL4批量小瓶数)                             500             760制造规模*                          S-i             S-i阿霉素盐酸盐批号                    6017G703        6017G703*Lab＝试验室S-i＝半工业的表39-稳定性研究，在5％葡萄糖溶液中的批试验
                     批号TF/23270         TF/23273             6001MA批特点每瓶表阿霉素盐酸盐(毫克)                   10                     10                 10pH                         2.7                    3.5                2.9制剂号                     FI7701/IL5             FI7701/IL5         FI7701/IL5批量小瓶数                     564                    573                553制造规模*                 Lab                    Lab                S-i阿霉素盐酸盐批号           6016G669               6016G669           6016G669
                       批号6001MB             6001MC批特点每瓶表阿霉素盐酸盐(毫克)                   20                     50pH                         3.1                    2.6制剂号                     FI7701/IL6             FI7701/IL7批量小瓶数                     500                    751制造规模*                 S-i                    S-i阿霉素盐酸盐批号           6017G703               6017G703*Lad＝实验室S-i＝半工业化的表40-稳定性研究，在注射用水中的批试验
                批号TF/23176批特点每瓶表阿霉素盐酸盐(毫克)                                  10pH                                        3.0制剂号                                    F17701/IL1批规模小瓶数                                    430制造规模*                                实验室表阿霉素盐酸盐批号                                      5009D646
表41-稳定性研究，用于表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成的即可使用
的溶液的包装
    批号包装     TF/23274     TF/23275     6001LA     6001LB     6001LC
小瓶玻璃类型 1 1 1 1 1
小瓶最高容量 10ml 10ml 10ml 14ml 39ml
胶塞 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面
铝盖     铝     铝     铝     铝     铝
表42-稳定性研究，用于表阿霉素盐酸盐在5％葡萄糖中的已制成的即可使用的
 溶液的包装
  批号包装     TF/23270     TF/23273     6001MA     6001Mb     6001MC
  小瓶玻璃类型 1 1 1 1 1
  小瓶最高容量 10ml 10ml 10ml 14ml 39ml
胶塞 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面 氯丁基橡胶聚四氟乙烯涂面
  铝盖     铝     铝     铝     铝     铝
表43-稳定性研究，用于表阿霉素盐酸盐在注射用水中的已制成的
即可使用的溶液的包装
  批号包装 TF/23176
  小瓶玻璃类型 1
  小瓶最高容量 10ml
胶塞 氯丁基橡胶聚四氟乙烯涂面
  铝盖     铝
表44-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成的即可
使用的溶液在4℃的稳定性数据小瓶直立贮存批号                                   初值               6个月剂量                                   对照
                 *                 2.218TF/23274             **                100.0               n.d.10mg                 ***               2.7
                 ****              2.9
                 *                 2.223TF/23275             **                100.0               n.d.10mg                 ***               2.8
                 ****              3.5
                 *                 2.155               2.2666001LA               **                100.0               105.210mg                 ***               1.9                 3.3
                 ****              3.0                 3.0
                 *                 1.961               2.0136001LB               **                100.0               102.620mg                 ***               1.2                 3.3
                 ****              3.1                 3.1
                 *                 2.072               2.0866001LC               **                100.0               100.750mg                 ***               1.4                 3.0
                 ****              2.7                 2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初始值％***有关物质％****pHn.d.＝未测表45-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成
的即可使用的溶液在8℃下的稳定性数据
小瓶直立贮存批                                  初值           1个月     3个月      6个月剂量                                对照
             *                  2.218TF/23274         **                 100.0           n.d.      n.d.       n.d.10mg             ***                2.7
             ****               2.9
             *                  2.223TF/23275         **                 100.0           n.d.      n.d.       n.d.10mg             ***                2.8
             ****               3.5
             *                  2.155           2.165     2.143      2.1826001LA           **                 100.0           100.5     99.4       101.310mg             ***                1.9             3.8       2.9        3.7
             ****               3.0             3.0       3.0        3.0
             *                  1.961           1.983     1.9496001LB           **                 100.0           101.1     99.4       n.d.20mg             ***                1.2             2.6       3.0
             ****               3.1             3.1       3.0
             *                  2.072           2.095     2.116      2.0126001LC           **                 100.0           101.1     102.1      97.150mg             ***                1.4             2.4       3.2        3.7
             ****               2.7             2.7       2.7        2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初始值％***相关的物质％****pHn.d.＝未测表46-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成
的即可使用的溶液在4℃下的稳定性数据
小瓶倒立贮存批                                     初值                         6个月剂量                                   对照
            *                     2.218                        2.247TF/23274        **                    100.0                        101.310mg            ***                   2.7                          4.1
            ****                  2.9                          2.9
            *                     2.223                        2.235TF/23275        **                    100.0                        100.510mg            ***                   2.8                          3.6
            ****                  3.5                          3.6
            *                     2.155                        2.2196001LA          **                    100.0                        103.010mg            ***                   1.9                          3.5
            ****                  3.0                          3.0
            *                     1.961                        1.9556001LB          **                    100.0                        99.720mg            ***                   1.2                          2.8
            ****                  3.1                          3.1
            *                     2.072                        2.1546001LC          **                    100.0                        104.050mg            ***                   1.4                          3.0
            ****                  2.7                          2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关物质****pH表47-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成
 的即可使用的溶液在8℃下的稳定性数据
  小瓶倒立贮存批                            初值        1个月          3个月        6个月剂量                          对照
             *             2.218      2.223         2.139        2.227TF/23274         **            100.0      100.2         96.4         100.410mg             ***           2.7        2.5           3.9          3.7
             ****          2.9        2.8           2.9          2.9
             *             2.223      2.226         2.121        2.228TF/23275         **            100.0      100.1         95.4         100.210mg             ***           2.8        2.9           5.0          5.9
             ****          3.5        3.5           3.5          3.5
             *             2.155      2.220         2.156        2.2156001LA           **            100.0      103.0         100.0        102.810mg             ***           1.9        3.6           3.3          3.6
             ****          3.0        3.0           3.0          3.0
             *             1.961      2.019         1.951        1.9806001LB           **            100.0      102.9         99.5         101.020mg             ***           1.2        2.8           3.5          3.6
             ****          3.1        3.1           3.0          3.1
             *             2.072      2.066         2.132        2.0606001LC           **            100.0      99.7          102.9        99.450mg             ***           1.4        2.8           3.3          3.2
             ****          2.7        2.7           2.6          2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关物质％****pH表48-表阿霉素盐酸盐在0.9氯化钠注射液中的已制成
的即可使用的溶液，在15℃下的稳定性数据
小瓶倒立贮存批                         初值         1个月           3个月         6个月剂量                       对照
           *           2.218        2.235           2.173         2.081TF/23274       **          100.0        100.8           98.0          93.810mg           ***         2.7          4.1             3.9           5.4
           ****        2.9          2.9             2.9           2.9
           *           2.223        2.221           2.108TF/23275       **          100.0        99.9            94.8          n.d.10mg           ***         2.8          3.2             5.0
           ****        3.5          3.5             3.4
           *           2.155        2.210           2.121         2.0886001LA         **          100.0        102.5           98.4          96.810mg           ***         1.9          3.4             3.5           n.d.
           ****        3.0          3.0             3.0           3.0
           *           1.961        2.009           1.9156001LB         **          100.0        102.4           97.6          n.d.20mg           ***         1.2          3.6             3.7
           ****        3.1          3.1             3.0
           *           2.072        2.052           2.081         2.0366001LC         **          100.0        99.0            100.4         98.350mg           ***         1.4          2.6             4.0           3.1
           ****        2.7          2.7             2.6           2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关物质％****pH表49-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制成
的即可使用的溶液，在27℃的稳定性数据
  小瓶倒立贮存批                             初值            1个月            3个月剂量                           对照
            *              1.28            2.111            1.941TF/23274        **             100.0           95.2             87.510mg            ***            2.7             5.4              7.1
            ****           2.9             2.9              2.9
            *              2.223           2.041            1.729TF/23275        **             100.0           91.8             77.810mg            ***            2.8             6.5              15.3
            ****           3.5             3.5              3.2
            *              2.155           2.144            1.9386001LA          **             100.0           99.5             89.910mg            ***            1.9             5.2              9.9
            ****           3.0             3.0              3.0
            *              1.961           1.867            1.7386001LB          **             100.0           95.7             88.820mg            ***            1.2             4.1              8.5
            ****           3.1             3.1              3.0
            *              2.072           2.009            1.8666001LC          **             100.0           96.9             90.150mg            ***            1.4             4.1              9.1
            ****           2.7             2.7              2.6*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pH表50-表阿霉素盐酸盐在0.9％氯化钠注射液中已制成的
即可使用的溶液，在250呎烛光下的稳定性数据
小瓶倒立贮存批                              初值                  1个月               3个月剂量                            对照
               *           2.218                   2.059              1.764TF/23274           **          100.0                   92.8               79.510mg               ***         2.7                     5.3                11.3
               ****        2.9                     2.9                2.9
               *           2.223                   1.974              1.363TF/23275           **          400.0                   88.8               61.310mg               ***         2.8                     11.3               15.1
               ****        3.5                     3.5                3.1
               *           2.155                   1.984              1.6676001LA             **          100.0                   92.1               77.410mg               ***         1.9                     5.0                12.6
               ****        3.0                     3.0                3.0
               *           1.961                   1.864              1.6266001LB             **          100.0                   95.0               82.920mg               ***         1.2                     5.9                10.7
               ****        3.1                     3.0                2.9
               *           2.072                   2.118              2.0026001LC             **          100.0                   102.2              96.650mg               ***         1.4                     2.6                5.9
               ****         2.7                     2.7                2.6*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质****pH表51-表阿霉素盐酸盐在0.9％氯化钠注射液中的已制
成的即可使用的溶液，在-20℃的稳定性数据
小瓶倒立贮存批                     初值               1个月             3个月剂量                   对照
           *       2.218TF/23274       **      100.0               n.d.             n.d.10mg           ***     2.7
           ****    2.9
           *       2.223TF/23275       **      100.0               n.d.             n.d.10mg           ***     2.8
           ****    3.5
           *       2.155               2.185            2.1316001LA         **      100.0               101.4            98.910mg           ***     1.9                 2.8              3.0
           ****    3.0                 3.0              3.0
           *       1.961               1.991            1.9586001LB         **      100.0               101.5            99.820mg           ***     1.2                 3.0              3.3
           ****    3.1                 3.0              3.0
           *       2.072               2.049            2.1846001LC         **      100.0               98.9             105.450mg           ***     1.4                 2.9              3.3
           ****    2.7                 2.7              2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pHn.d.＝未测定表52-表阿霉素盐酸盐在5％葡萄糖溶液中的已制
成的即可使用的溶液，在4℃下的稳定性数据
小瓶直立贮存批                               初值                   6个月剂量                             对照
             *               2.178TF/23270         **              100.0                   n.d.10mg             ***             3.7
             ****            2.7
             *               2.132TF/23273         **              100.0                   n.d.10mg             ***             3.1
             ****            3.5
             *               2.131                   2.1736001MA           **              100.0                   102.010mg             ***             2.0                     4.0
             ****            3.0                     3.0
             *               1.973                   1.9176001MB           **              100.0                   97.520mg             ***             1.7                     4.0
             ****            3.1                     3.1
             *               2.091                   2.1836001MC           **              100.0                   104.450mg             ***             1.1                     3.3
             ****            2.7                     2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关物质****pHn.d.＝未测表53-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的即可
使用的溶液，在8℃下的稳定性数据
         小瓶直立贮存批                           初值    1个月       3个月       6个月剂量                         对照
            *            2.178TF/23270        **           100.0    n.d.        n.d.        n.d.10mg            ***          3.7
            ****         2.9
            *            2.132TF/232273       **           100.0    n.d.        n.d.        n.d.10mg            ***          3.1
            ****         3.5
            *            2.131    2.133       2.185       2.1526001MA          **           100.0    97.8        102.5       101.010mg            ***          2.0      2.9         3.1         4.4
            ****         3.0      3.0         3.0         3.0
            *            1.973    1.979       1.936       1.9346001MB          **           100.0    100.3       98.1        98.420mg            ***          1.7      2.2         3.3         3.3
            ****         3.1      3.1         3.0         3.1
            *            2.091    2.093       2.073       2.0536001MC          **           100.0    100.1       99.1        98.250mg            ***          1.1      3.3         2.5         3.3
            ****         2.7      2.6         2.6         2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pHn.d.＝未测表54-表阿霉素盐酸盐在5％葡萄糖溶液中的已制
成的即可使用的溶液，在4℃下的稳定性数据
小瓶倒立贮存批                                  初值                     6个月剂量                                对照
              *                 2.178                    2.171TF/23270          **                100.0                    99.710mg              ***               3.7                      4.3
              ****              2.7                      2.7
              *                 2.132                    2.214TF/23273          **                100.0                    103.810mg              ***               3.1                      n.d.
              ****              3.5                      3.5
              *                 2.131                    2.2416001MA            **                100.0                    105.210mg              ***               2.0                      3.6
              ****              3.0                      3.0
              *                 1.973                    1.8996001MB            **                100.0                    96.620mg              ***               1.7                      2.9
              ****              3.1                      3.1
              *                 2.091                    2.1286001M1C           **                100.0                    101.850mg              ***               1.1                      3.0
              ****              2.7                      2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pH表55-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的即
可使用的溶液在8℃的稳定数据
/小瓶倒立贮存批                        初值        1个月        3个月        6个月剂量                      对照
             *        2.178      2.207          2.201      2.228TF/23270         **       100.0      101.3          101.0      102.310mg             ***      3.7        3.9            3.8        2.6
             ****     2.7        2.7            2.7        2.7
             *        2.132      2.189          2.143      2.149TF/23273         **       100.0      102.7          100.5      100.810mg             ***      3.1        3.2            4.3        2.8
             ****     3.5        3.5            3.4        3.5
             *        2.131      2.184          2.179      2.2276001MA           **       100.0      100.1          99.9       104.410mg             ***      2.0        3.2            3.0        3.6
             ****     3.0        3.0            3.0        3.0
             *        1.973      1.964          1.913      1.8936001MB           **       100.0      99.5           97.0       96.320mg             ***      1.7        2.3            3.6        3.5
             ****     3.1        3.0            3.0        3.1
             *        2.091      2.060          2.078      2.1616001MC           **       100.0      98.5           99.4       103.350mg             ***      1.1        2.9            2.9        3.5
             ****     2.7        2.6            2.6        2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pH表56-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的
即可使用的溶液，在15℃下的稳定数据
小瓶倒立贮存批                   初值            1个月       3个月          6个月剂量                 对照
          *      2.178           2.219        2.170          2.237TF/23270      **     100.0           101.9        99.6           102.710mg         ***    3.7             3.4          4.3            2.7
          ****   2.7             2.7          2.6            2.7
          *      2.132           2.153        2.079          2.119TF/23273      **     100.0           101.0        97.5           99.410mg         ***    3.1             3.4          4.5            n.d.
          ****   3.5             3.5          3.4            3.4
          *      2.131           2.158        2.155          2.1336001MA       **     100.0           98.9         98.8           100.110mg         ***    2.0             3.3          2.4            4.5
          ****   3.0             3.0          3.0            3.0
          *      1.973           1.978        1.8936001MB       **     100.0           100.2        95.9           n.d.20mg         ***    1.7             2.0          3.7
          ****   3.1             3.1          3.0
          *      2.091           2.121        2.066          2.0616001MC        **     100.0           101.4        98.8           98.550mg          ***    1.1             3.2          2.9            5.1
          ****   2.7             2.6          2.7            2.7*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pH表57-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的
即可使用的溶液，在27℃下的稳定性数据
小瓶倒立贮存批                    初值           1个月           3个月剂量                  对照
          *       2.178          2.113            2.052TF/23270     **      100.0          97.0             94.210mg         ***     3.7            4.7              4.7
          ****    2.7            2.7              2.7
          *       2.132          2.068            1.944TF/23273     **      100.0          97.0             91.210mg         ***     3.1            6.0              7.5
          ****    3.5            3.5              3.3
          *       2.131          2.144            2.0336001MA       **      100.0          96.9             93.210mg         ***     2.0            3.2              7.3
          ****    3.0            3.0              3.0
          *       1.973          1.919            1.7966001MB       **      100.0          97.3             91.120mg         ***     1.7            2.1              6.2
          ****    3.1            3.0              3.0
          *       2.091          2.096            1.8966001MC       **      100.0          100.6            90.750mg         ***     1.1            3.0              6.6
          ****    2.7            2.6              2.6*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pH表58-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的即可
使用的溶液在250呎烛光下的稳定性数据
  小瓶倒立贮存批                       初值              1个月            3个月剂量                     对照
            *          2.178             2.132            2.003TF/23270      **         100.0             97.9             92.010mg          ***        3.7               6.7              9.2
            ****       2.7               2.7              2.7
            *          2.132             2.046            1.796TF/23273      **         100.0             96.0             84.210mg          ***        3.1               5.8              10.3
            ****       3.5               3.4              3.2
            *          2.131             2.079            1.9886001MA        **         100.0             95.3             91.110mg          ***        2.0               3.7              8.2
            ****       3.0               3.0              3.0
            *          1.973             1.894            1.8036001MB        **         100.0             96.0             91.420mg          ***        4.7               2.0              5.6
            ****       3.1               3.0              3.0
            *          2.091             2.022            1.9886001MC        **         100.0             96.7             95.150mg          ***        1.1               4.0              4.2
            ****       2.7               2.6              2.6*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质****pH表59-表阿霉素盐酸盐在5％葡萄糖溶液中的已制成的即可
使用的溶液，在-20℃下的稳定性数据
小瓶倒立贮存批                         初值           1个月             3个月剂量                       对照
            *          2.178TF/23270        **         100.0           n.d.              n.d.10mg            ***        3.7
            ****       2.7
            *          2.132TF/23273        **         100.0           n.d.              n.d.10mg            ***        3.1
            ****       3.5
            *          2.131           2.168             2.1626001MA          **         100.0           99.4              99.110mg            ***        2.0             2.2               3.3
            ****       3.0             3.0               3.0
            *          1.973           1.965             1.9946001MB          **         100.0           100.6             101.420mg            ***        1.7             2.6               3.8
            ****       3.1             3.0               3.0
            *          2.091           2.114             2.0906001MC          **         100.0           101.9             99.950mg            ***        1.1             2.5               2.6
            ****       2.7             2.6               2.6*表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pHn.d.＝未测表60-表阿霉素盐酸盐在注射用水中的已制成的即可使用
的溶液的稳定性数据
批号TF/23176
小瓶直立贮存贮存                                     时    间      (月数)温度    试验                   0        1         2      3         6       9       12
     *                     2.079   2.061           2.059-20℃    **                    100.0   99.1      n.d.  99.0       n.d.    n.d.
     ***                   4.0     3.8             4.9
     ****                  3.0     3.1             3.2
     *                     2.079                   2.062      2.061           1.9764℃      **                    100.0   n.d.      n.d.  99.2       99.1    n.d.    95.0
     ***                   4.0                     3.7        3.4             6.7
     ****                  3.0                     3.2        3.2             3.1
     *                     2.079   2.041     2.043 1.995      1.986           1.9508℃      **                    100.0   98.2      98.3  90.0       95.5    n.d.    93.8
     ***                   4.0     3.6       3.8   4.0        3.4             6.7
     ****                  3.0     3.0       3.0   3.1        3.2             3.1
     *                     2.079   2.001     1.989 1.990      1.923           1.75715℃     **                    100.0   96.2      95.7  95.7       92.5    n.d.    84.5
     ***                  4.0     3.7       3.9   3.9        3.5             8.8
     ****                  3.0     3.0       3.0   3.1        3.2             3.1
     *                     2.079   1.977     1.879 1.830      1.48027℃     **                    100.0   95.1      90.4  88.0       71.2    n.d.
     ***                   4.0     5.0       6.8   6.9        9.0
     ****                  3.0     3.0       3.1   3.1        3.1* 表阿霉素盐酸盐测定(毫克/毫升)**表阿霉素盐酸盐初值％***相关的物质％****pHn.d.＝未测
表61-表阿霉素盐酸盐在注射用水中的已制成的即可使用
的溶液的稳定性数据
批号TF/3176
                小瓶倒立贮存贮存                                 时    间      (月数)温度        试验       0        1         2       3       6      9     12
         *        2.079    2.052            2.060-20℃      **       100.0    98.7     n.d.    99.1     n.d.    n.d.  n.d.
         ***      4.0      3.7              4.6
         ****     3.0      3.1              3.2
         *        2.079                     2.045    2.067
4℃      **       100.0    n.d.     n.d.    98.4     99.4    n.d.  n.d.
         ***      4.0                       3.6      2.9
         ****     3.0                       3.2      3.2
         *        2.079   2.033     2.039   2.022    1.977
8℃      **       100.0   97.8      98.1    97.3     95.1    n.d.  n.d.
         ***      4.0     3.5       3.8     3.7      3.1
         ****     3.0     3.0       3.0     3.1      3.2
         *        2.079   1.992     1.994   1.994    1.344         1.759
15℃     **       100.0   95.8      95.9    95.9     93.0    n.d.  84.6
         ***      4.0     3.6       3.9     4.6      4.4           8.6
         ****     3.0     3.0       3.0     3.1      3.2           3.1
         *        2.079   1.964     1.836   1.779    1.568
27℃     **       100.0   94.5      88.3    85.6     75.4
         ***      4.0     5.0       7.9     6.9      7.4
         ****     3.0     3.0       3.1     3.1      3.1
         *        2.079  1.923              1.778
R.T.+    **       100.0  92.5       n.d.    85.5
100F.C.  ***      4.0    4.8                7.5
         ****     3.0    3.1                3.1
         *        2.079  1.886              1.493
R.T.+    **       100.0  90.7       n.d.    71.8
250F.C.  ***      4.0    6.6                13.5
         ****     3.0    3.0                3.0*  表阿霉素盐酸盐测定(毫克/毫升)** 表阿霉素盐酸盐初值％*** 相关的物质％****pHn.d.＝未测RT＝室温FC＝呎烛光

Claims (9)

1.一种制造贮存稳定、无菌、无致热原、可注射的蒽环苷溶液的方法，该方法包括将一种生理上可接受的、非冻干形式的、选自阿霉素盐酸盐、4′-表阿霉素盐酸盐和4-去甲氧柔红霉素的蒽环苷盐溶于生理上可接受的水性溶剂中，以达到蒽环苷的浓度为0.1-50mg/ml，而该方法以所得到的溶液是无菌的和无致热原的方式实施，其特征在于加入一种甘氨酸缓冲液以调节pH值为2.5至3.5。
2.根据权利要求1的方法，其中在用所述的甘氨酸缓冲液来调节溶液的pH以后，将溶液通过无菌的过滤器。
3.根据权利要求1或2的方法，其中将所得到的溶液引入一个容器中然后密封。
4.根据权利要求1或2的方法，其中该蒽环苷是阿霉素或4’-表-阿霉素。
5.根据权利要求1或2的方法，其中将pH值调节到3至3.5。
6.根据权利要求1或2的方法，其中将pH值调节到2.5至3。
7.根据权利要求1或2的方法，其中在蒽环苷盐已溶于所述的溶剂中之后并在加入甘氨酸缓冲液以调节pH之前加入共溶剂、张力调节剂、防腐剂和可作药用的螯合剂中选出的一种或多种配方辅药。
8.根据权利要求1或2的方法，其中在该蒽环苷盐已溶于所述的溶剂中之后并在加入甘氨酸缓冲液调节pH值之前加入葡萄糖、乳糖、山梨糖醇和甘露糖醇中之一种作为张力调节剂。
9.根据权利要求1或2的方法，其中生理可接受的水性溶剂是水或生理盐水或5％葡萄糖水溶液。
CN87108225A 1986-12-05 1987-12-03 已制成的可用的注射用蒽环苷类抗癌剂的溶液 Expired - Lifetime CN1058391C (zh)

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US8227430B2 (en) * 2007-09-04 2012-07-24 Meiji Seika Pharma Co., Ltd Injectable, injection solution, and injection kit preparation
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