CN1152713C - 含有海藻糖的干燥的血液因子组合物 - Google Patents

含有海藻糖的干燥的血液因子组合物 Download PDF

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CN1152713C
CN1152713C CNB961926600A CN96192660A CN1152713C CN 1152713 C CN1152713 C CN 1152713C CN B961926600 A CNB961926600 A CN B961926600A CN 96192660 A CN96192660 A CN 96192660A CN 1152713 C CN1152713 C CN 1152713C
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B·J·罗色尔
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Abstract

一种稳定的血液因子组合物，它在不含有人血清白蛋白的条件下，含有稳定化量的海藻糖，以提供一种可稳定至60℃的制品。

Description

含有海藻糖的干燥的血液因子组合物
技术领域
本发明涉及血液因子的干燥的组合物，用于用水或水溶液重建(reconstitution)。
背景技术
血液因子，特别是因子VIII和因子IX，是目前治疗由缺少适当因子引起的疾病，特别是血友病的标准治疗药剂。血液因子一般是通过各种提取技术来源于人的血液的，例如EP-A-0083483中所公开的，或者通过在基因修饰的微生物中表达得到，例如EP-A-0160457和EP-A-0182448中所公开的。
血液因子制品(例如因子VIII)是非常敏感、不稳定的蛋白。它们通常是以溶于合适的缓冲液中的，冰冻的溶液的形式提供的，更一般地，它们是以冻干的粉末形式提供的。但甚至冻干的粉末在保存时也必须保持在低温下。为了使冻干的物质稳定，商业制品含有稳定化蛋白，特别是人血清白蛋白(HSA)。制备在环境温度和巴氏消毒(例如60℃)下稳定的，不含HSA的干燥的血液因子组合物被认为是不可能的。但是，HSA的存在将带来不可忽视的纯化方面的问题，因为蛋白不被病毒污染这一点是必需的。克服这些问题的重组HSA的应用是昂贵的。
发明内容
已知海藻糖是敏感蛋白的高效稳定剂，如US-A-4891319中所公开的，能够使蛋白在冰点以上的温度干燥。我们现已发现，在完全不含有HSA的条件下，如果用海藻糖来稳定血液因子制品，该制品不仅可以在冷冻或不冷冻的条件下干燥，并且甚至在60℃温度下持续一定时间后也是稳定的。因此，根据本发明，我们提供了稳定的干燥的血液因子组合物，该组合物含有稳定化量的海藻糖，不含有白蛋白。
通常可以应用任意稳定化量的海藻糖，过量一般不会带来问题。实际上，海藻糖的存在有助于再水化过程，它用于注射时是生理可接受的，能够迅速地被代谢成葡萄糖。该组合物对因子VIII的制剂是特别适用的，该制剂也可包含适当的缓冲盐或离子增强盐，特别是钙源。一般地，每单位的因子VIII对应大约1.0至1.5毫克钙离子的比率是合适的。
其他缓冲或改性剂(例如组氨酸)也可存在于干燥的物质中，用于重建成注射液。但是，我们发现盐(特别是氯化钠)的存在水平可影响干燥制品的保存性。用于注射的商业制品被认为需要具有等渗盐浓度。但是，冻建成注射液。但是，我们发现盐(特别是氯化钠)的存在水平可影响干燥制品的保存性。用于注射的商业制品被认为需要具有等渗盐浓度。但是，冻干的制剂最好是高渗的，典型地含有大约500mM NaCl(等渗NaCl＝150mM)，这被认为有助于稳定血液因子。结果，商业性冻干制剂通常具有高的盐含量，需用合适量的无菌水重建以得到等渗的溶液用于注射。
显著减少的盐含量对本发明的干燥的物质是优选的，需要干燥的每毫升大约500单位的因子III溶液通常优选地含有少于200mM，例如75-150mM的NaCl，特别是大约100mM，但是可低于例如20-50mM，特别是大约22-30mM。低盐制备物具有更高的干燥稳定性。可用盐溶液而不是常规的水将干燥制品重建到所需的盐浓度。海藻糖与盐的摩尔比通常应当高于1∶1，特别是高于2.5∶1，例如高于10∶1，优选地高于12.5∶1。
可通过干燥血液因子的适当溶液得到干燥的组合物，所述血液因子溶液含有正确比例的海藻糖和其他所需的成分。通常，被干燥的溶液应仅仅含有重建的注射溶液中所需的全部成分，虽然用于干燥的溶液不必处于同样的稀释度。典型地，每毫升用于干燥的溶液含有1-1000单位的因子III。干燥的方法可包括冻干、真空干燥和喷雾干燥。本发明特别优选的方法包括在不高于25℃，优选不高于10℃的温度下进行真空干燥，以形成泡沫，使暴露表面和干燥效果最大化。优选地，本发明的组合物每单位的血液因子含有0.15至2.5毫克的海藻糖。
下述实施例将进一步阐明本发明。
                      具体实施方式
实施例1
重组的因子VIII是以深度冷冻溶液的形式得到的，含有大约2000-2500单位/毫升，溶于制造者的高盐缓冲剂中。融化的溶液被透析，所用缓冲液含有500mM NaCl，15mM CaCl2和10mM组氨酸，pH6.8。在同样缓冲液中稀释透析后的蛋白，但是加入海藻糖，终浓度为每毫升500单位，10％重量比的海藻糖，pH6.8。该溶液以1毫升的等分试样被真空干燥。真空度从大气压逐级减少到4Pa(30mTorr)，以避免样品冷冻。在形成泡沫之前，样品的温度不允许超过12℃，在形成泡沫之后，温度保持在低于30℃。总的干燥时间是24小时至28小时。
样品在40℃下保存0、1.5、3和6个月，然后在进行活性检测之前用5毫升等分试样的无菌蒸馏水重建。结果显示于下表，与含有HSA的商品化冻干制品进行对比。受试样品和商品化样品都具有高的盐含量。干燥后的结果显示，在不含有HSA而含有海藻糖的条件下，虽然可以成功地干燥因子VIII，但即使在含有HSA时，高的盐含量对于长期保存也是不利的。
           初始活性的百分数
    时间(月)     样品     商业制品
    01.536     100.086.875.176.6     100.095.371.263.6
实施例2
如实施例1所述干燥样品，但所使用的缓冲制剂包含100mM NaCl，15mM CaCl2，15mM组氨酸和1.27摩尔海藻糖(43.5w/v)，并在重建之前保存在60℃。结果显示在下表中，其中活性是在ACL 100自动凝度计(Instrumentation Laboratory SpA，Milan，Italy)上测量的。即使在60℃下保存4周之后，具有低盐含量的受试样品也没有显示出明显的活性损失。
   恢复的初始活性的百分数
    湿性对照     1000
    干燥后2周4周     95.596.096.8
实施例3
制备含有如下不同盐浓度的两种制剂：
            制剂A                         制剂B
NaCl                0.13％         NaCl            1.03％
CaCl2              0.011％        CaCl2          0.011％
L-组氨酸            0.12％         L-组氨酸        0.12％
Tris                0.002％        Tris            0.002％
Tween 80            0.002％        Tween 80        0.002％
PEG 3350            0.004％        PEG 3350        0.004％
海藻糖              7.5％          海藻糖          7.5％
因子VIII            50U/ml         因子VIII        50U/ml
加水至100％                        加水至100％
将10毫升的制剂分配到各个30毫升的瓶中，使得因子VIII的浓度为500单位/瓶。
冻干是在Laconco(Lyph-lock 12 stoppering)冻干机中进行的。开始时，样品被冷却至-40℃，然后在加温至-35℃之前被置于真空。80小时之后，以2.5℃/小时的速率将样品加温，直到搁板温度达到25℃。然后在封闭之前，在真空下将样品保持在25℃两小时，并从干燥机中移出。
干燥之后，用10毫升水将样品重新水化，测定两次(测定l和2)因子VIII的浓度。结果由下表给出，以因子VIII浓度相对于预补充(prefill)对照(在-70℃下冷冻)的百分数表示。从该结果可以看出，因子VIII可以在不含有HSA的，基于海藻糖的制剂中被成功地冻干。
    样品     测定1     测定2
    制剂A制剂B     77％9l％     85％94％

Claims (13)

1.一种稳定的、冻干的血液因子组合物，其含有稳定化量的海藻糖，不含有白蛋白，所述血液因子是因子VIII。
2.权利要求1的组合物，其中每单位的血液因子含有0.15至2.5毫克的海藻糖。
3.权利要求1或2的组合物，其含有NaCl，其中海藻糖与NaCl的摩尔比高于1∶1。
4.权利要求3的组合物，其中每摩尔氯化钠含有超过2.5摩尔的海藻糖。
5.权利要求3的组合物，其中每摩尔氯化钠含有超过10摩尔的海藻糖。
6.权利要求1的组合物，其中每单位的因子VIII含有1.0至1.5微克的钙离子。
7.制备权利要求1的组合物的方法，其中含有海藻糖的血液因子的水溶液是在不超过25℃的温度下被干燥的。
8.权利要求7的方法，其中温度不超过10℃。
9.制备权利要求1的组合物的方法，其包括使因子VIII的水溶液干燥，所述溶液含有海藻糖和每单位因子VIII低于0.4mM的NaCl。
10.制备用于注射的含有血液因子的治疗组合物的方法，其包括重建权利要求1的组合物。
11.权利要求10的方法，其中组合物是用水重建的。
12.权利要求10的方法，其中组合物是用盐水重建的。
13.权利要求1的组合物在制备注射用含血液因子的治疗组合物中的用途，所述组合物用于治疗血友病。
CNB961926600A 1995-01-19 1996-01-19 含有海藻糖的干燥的血液因子组合物 Expired - Lifetime CN1152713C (zh)

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