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CN1066065C - 干扰素溶液 - Google Patents

干扰素溶液 Download PDF

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CN1066065C
CN1066065C CN96100545A CN96100545A CN1066065C CN 1066065 C CN1066065 C CN 1066065C CN 96100545 A CN96100545 A CN 96100545A CN 96100545 A CN96100545 A CN 96100545A CN 1066065 C CN1066065 C CN 1066065C
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G·格罗斯
S·D·特佐
S·K·库玛
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Abstract

一种干扰素水溶液，含有
(a)一种干扰素α；
(b)一种非离子洗涤剂；
(c)一种调节pH在4.5-5.5的缓冲液；
(d)苄醇；以及，可选择地
(e)一种等渗剂。

Description

干扰素溶液
本发明涉及一种适合于非肠道用药的干扰素α水溶液。干扰素溶液的生产涉及许多问题，这些问题是由有效成分对物理和化学因素的敏感性引起的而且至今尚未得到满意的解决。与其它蛋白质相似，水溶液中的干扰素受到化学降解机理的作用如蛋白酶解、氧化、二硫化物交换、寡聚、脱酰胺作用和β-消去，以及物理机理的作用如聚集、沉淀和吸附。因此，干扰素含有用来抵消这些作用的添加剂。例如，人血清白蛋白(HSA)在商用制品中用作稳定剂，但这也有问题，因为有病毒污染的危险和聚集体的形成，这反过来会导致抗体形成。所以，已推荐一些干扰素溶液，它们避免使用HSA，而且除其它物质以外，还含有其它辅助剂即非离子洗涤剂(参见国际专利申请WO89/04177和日本专利申请61-277633)。而且还已知，保持特定的pH值对干扰素溶液的稳定很重要。例如，在专利申请WO89/04177提到4.0-6.0的pH范围。最后，与在其它注射液中一样，还需要赋形剂，例如，用来调节等渗溶液的试剂，以及防腐剂。
由于干扰素活性高而且以最小浓度存在于药物制剂中，所以干扰素制品的稳定性和保证有效成分的恒定浓度尤为重要。已经发现，为保证最佳利用性能，干扰素溶液的赋形剂必须从众多有潜力的适宜试剂中精心选择而且相互间必须相配。例如，在pH5-6下干扰素α2a在玻璃表面上的吸附最大，所以这样的pH原则上似乎是不利的。另一方面，在此pH下共价降解反应进行得最小。商用的用HSA稳定的溶液pH为7。许多不相关的因素以不可预料的方式影响干扰素溶液的利用性能。
现已发现，含有
(a)一种干扰素α；
(b)一种非离子洗涤剂；
(c)一种调节pH为4.5-5.5的缓冲液；
(d)苄醇；以及，可选择地
(e)一种等渗剂的不含HSA的干扰素α水溶液显示出最佳利用性能，例如贮藏稳定性和公布量有效成分的生物利用率。
对本发明中的应用，可使用任何干扰素α，例如，欧洲专利No.43980中公开的干扰素α(其中称为成熟人白细胞干扰素A，也参见J.Pharm.Biomed，Analysis Vol.7，No.2，233-238(1989))。
本发明中采用的干扰素α可以结合到聚合物上，例如聚亚烷基二醇(取代的或未取代的)如聚乙二醇上，形成PEG-干扰素α。可用本技术中已知的各种接头完成这种结合，特别是用诸如欧洲专利申请EP-A-0510356和A-0593868中公开的那些接头。优选为聚乙二醇这样的聚合物的分子量可在300至30，000道尔顿之间变化，一或多种接头、优选一至三种接头结合到干扰素α上。用干扰素α2a形成优选的干扰素α结合物。
用于本发明的优选干扰素α是干扰素α2a和聚乙二醇化(PEG)干扰素α2a。优选的是，按照本发明的溶液每毫升含有106-108、特别是1-36×106国际单位(IU)的干扰素α。
本发明制剂中使用的非离子洗涤剂的例子有吐温，例如吐温20或吐温80(聚氧乙烯(20)山梨糖醇酐一油酸酯)。本发明溶液中洗涤剂的量约为0.01-0.5mg/ml，优选0.05-0.2mg/ml。优选的缓冲物质是乙酸铵和乳酸钠。这些缓冲物质的适宜浓度约为10-15毫摩尔浓度。优选的是，把本发明的干扰素溶液调至pH5.0±0.1。本发明溶液中苄醇含量约为8-20mg/ml，特别是10mg/ml。可以特别考虑的等渗剂有氯化钠、甘露糖醇、甘油和氨基酸，特别是精氨酸、赖氨酸、组氨酸和蛋氨酸，以及乙醇胺。氯化钠或甘露糖醇是优选的。达到等渗所需的这些辅助剂的量取决于溶液的组成，并且可用常规技术确定。
用下列实施例进一步阐述本发明。
实施例1PEG-IFNα2a的制备PEG化：用10升由含120mM NaCl的5mM乙酸钠pH5.0组成的缓冲液透析IFNα2a两次。用摩尔比为3∶1的固体PEG试剂α-甲基-ω-〔2-〔〔(3-甲基-2-吡啶氧基)羰基〕氨基〕乙氧基〕聚(氧基-1，2-亚乙基)SRU110将1g材料(7.26mg/ml)PEG化。加入1/10体积的100mM四硼酸钠(pH10.7)，调节溶液的pH。室温下保温1小时后，加入1M甘氨酸至甘氨酸最终浓度为20mM，这样来终止反应。加入1/20体积的pH为4.0的1M乙酸钠，最终pH达5.0-6.0。用由40mM乙酸铵(pH4.5)组成的缓冲液将蛋白质溶液稀释4倍。纯化：以19ml/min流速向用40mM乙酸铵(pH4.5)平衡过的333ml CM纤维素柱上加入稀释的PEG化混合物。用8个柱体积的0-250mM NaCl梯度洗脱PEG化干扰素。按照SDS-PAGE结果，收集含PEG-IFN的级分。最终收集液含291mg，浓度为0.831mg/ml。收集的材料通过采用YM10(截留分子量10000)膜的Amicon搅拌细胞超滤单元浓缩至3.96mg/ml。
把浓缩材料(238mg)加到用40mM乙酸铵和125mM NaCl平衡过的6.3L S-200凝胶过滤柱上。流速为20ml/min。收集级分，用SDS-PAGE分析。S-200柱收集物含有480ml，浓度为0.48mg/ml。S-200柱收集物的一份等分试样用Amicon搅拌细胞浓缩至8.7mg/ml。该材料用于制备实施例4和5的制剂。
实施例2干扰素溶液组分                   每毫升的量干扰素α2a            1-36×106IU乙酸铵                     0.77mg氯化钠                     7.21mg苄醇                       10.0mg吐温80                      0.2mg乙酸达pH5.0±0.1             适量NaOH0.1N达pH5.0±0.1        适量注射用水                  达1.0ml生产方法：
无菌条件下，在带螺帽的50ml无菌聚丙烯管中的层流界面中制备制剂。赋形剂溶于注射用水中，调节pH，溶液中通入氮气。接着，在缓慢搅拌下加入干扰素本体溶液，如需要，再调pH，并且加入注射用水调至终体积。用低蛋白结合0.2μm过滤器把溶液无菌过滤到新的聚丙烯管中，注入2mlⅠ型小玻璃瓶中。向小瓶中通入氮气，用丁基橡胶瓶塞密封，该瓶塞是用惰性氟代聚乙烯膜压制成的。
实施例3干扰素溶液组分                        每毫升的量干扰素α2a                 1-36×106IU乙酸铵                          0.77mg甘油                            20.0mg苄醇                            10.0mg吐温80                           0.2mg乙酸达pH5.0±0.1                  适量NaOH0.1N达pH5.0±0.1             适量注射用水                       达1.0ml生产方法：如实施例2中所述。
实施例4干扰素溶液组分                        每毫升的量PEG-干扰素α2a             1-18×106IU乙酸铵                           1.0mg氯化钠                           5.0mg苄醇                            10.0mg吐温80                        0.05mg乙酸达pH5.0±0.1                适量NaOH0.1N达pH5.0±0.1           适量注射用水                     达1.0ml生产方法：如实施例2中所述。
实施例5干扰素溶液组分                      每毫升的量PEG-干扰素α2a           1-18×106IU乙酸铵                         1.0mg氯化钠                         3.0mg甘露糖醇                      30.0mg苄醇                          10.0mg吐温80                        0.05mg乙酸达pH5.0±0.1                适量NaOH0.1N达pH5.0±0.1           适量注射用水                     达1.0ml生产方法：如实施例2中所述。
为比较的目的，按照实施例2中给出的生产方法制备含3×106IU IFN α2a(A/3)、6×106IU IFN α2a(A/6)、9×106IU IFNα2a(A/9)、18×106IU IFN α2a(A/18)和36×106IU IFN α2a(A/36)的各种干扰素α2a溶液以及不含苄醇的相应溶液(B/3-36)，并于5、25和35℃下贮藏于暗处。贮藏3个月后，测定小瓶中干扰素α2a含量。通过0.45μm过滤器过滤样品，并用反相HPLC分析残留的主要成分干扰素α2a。HPLC法的标准偏差大约为5％。贮藏试验的结果列于表1。
表1
溶液/      下列温度下3个月后，主要成分IFN α2a的含量x106IU IFN              (以％计)α2a每ml            5℃    25℃    35℃A/3                93.8    60.7    43.5A/6                91.2    73.9    54.6A/9                94.1    80.3    61.6A/18               94.1    84.5    69.0A/36               91.9    88.5    71.1B/3                81.0    41.0     8.2B/6                88.9    55.1     8.5B/9                89.1    63.3    25.8B/18               92.2    62.8    26.8B/36               95.2    72.8    41.2
非常明显，在更高的贮藏温度下，溶液A的贮藏稳定性越高。
类似地，制备实施例4的含3×106IU聚乙二醇化干扰素α2a的聚乙二醇化IFN溶液(C/3)和相应的不含苄醇的溶液(D/3)，在5和25℃下贮藏24个月。贮藏试验的结果列于表2。
表2
溶液/        下列温度下24个月后，主要成分PEGx106PEGIUIFN        IFN α2a的含量(以％计)α2a每ml              5℃    25℃C/3                79.6    55.8D/3                60.1    5.8
从这些实验明显看出，加入苄醇而制备的溶液的贮藏稳定性更高。
实施例6
如上面所提及的，不含HSA的干扰素溶液公知于国际专利申请WO 89-04177和日本专利公开61-277633。把本发明溶液的稳定性与类似于已知溶液而制备的干扰素α2a溶液的稳定性进行比较。制备下列组成的溶液：溶液X干扰素α2a                    3-36×106IU乙酸铵               0.77mg氯化钠               8.77mg吐温80                0.3mg乙酸达pH5.0±0.1       适量NaOH0.1N达pH5.0±0.1  适量注射用水            达1.0ml溶液Y干扰素α2a      3-36×106IU琥珀酸               0.27mgDi-琥珀酸钠          0.73mgD-甘露糖醇           40.0mg土温80                0.1mgHCl0.1N达pH5.0±0.1   适量NaOH0.1N达pH5.0±0.1  适量注射用水            达1.0ml
溶液X和Y相当于上面文献中所述的溶液，采用3，6，9，18和36×106IU干扰素α2a代替干扰素β或干扰素β。各种贮藏温度下3个月后所得结果列于下表3中。
表3
溶液/    下列温度下3个月后，主要成分IFNx106IU IFN       α2a的含量(以％计)α2a5℃    25℃    35℃X/3              72.5    13.7     0.0X/6              72.8     3.1     0.0X/9              83.7    42.6     1.7X/18             86.5    50.5     2.6X/36             88.0    54.1     4.5Y/3              67.1    32.7     0.0Y/6              80.0    53.5     0.0Y/9              84.9    63.4     4.3Y/18             89.0    59.5    13.7Y/36             90.7    60.0    18.9
从这些数据清楚地看出，当把上面提到的技术水平的文献中所述的技术用于干扰素α2a时，不能达到可接受的贮藏稳定性。

Claims (6)

1．一种干扰素水溶液，含有(a)一种干扰素α；(b)一种非离子洗涤剂；(c)一种调节pH在4.5-5.5的缓冲液；(d)苄醇；以及，可选择地(e)一种等渗剂。
2．一种根据权利要求1的干扰素溶液，其中干扰素α的量为106-108IU/ml；非离子洗涤剂的量约为0.01-0.5mg/ml；缓冲液浓度约为10-15毫摩尔浓度；苄醇的量约为8-20mg/ml。
3.一种根据权利要求1或2的干扰素溶液，含有：(a)干扰素α2a或聚乙二醇-干扰素α2a；(b)聚氧乙烯(20)山梨糖醇酐一油酸酯；(c)乙酸铵或乳酸钠；(d)苄醇；以及(e)氯化钠、甘露糖醇、甘油、精氨酸、赖氨酸、组氨酸、蛋氨酸或乙醇胺。
4.一种根据权利要求1或2的干扰素溶液，每ml含有：(a)1-36×106IU的干扰素α2a；(b)0.2mg聚氧乙烯(20)山梨糖醇酐一油酸酯；(c)10mM乙酸铵或乳酸钠；(d)10mg苄醇；以及(e)用量足以提供一种等渗溶液的氯化钠。
5．一种根据权利要求1或2的干扰素溶液，每ml含有(a)1-36×106IU聚乙二醇-干扰素α2a；(b)0.05mg聚氧乙烯(20)山梨糖醇酐一油酸酯；(c)13mM乙酸铵；(d)10mg苄醇；以及(e)用量足以提供一种等渗溶液的氯化钠或甘露糖醇。
6．一种根据权利要求1-5任一项的干扰素溶液，pH为5.0+0.1。
CN96100545A 1995-04-06 1996-04-04 干扰素溶液 Expired - Lifetime CN1066065C (zh)

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