WO2016155650A1 - 一种快速测定人凝血因子viii成品中水分含量的方法 - Google Patents

一种快速测定人凝血因子viii成品中水分含量的方法 Download PDF

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WO2016155650A1
WO2016155650A1 PCT/CN2016/078105 CN2016078105W WO2016155650A1 WO 2016155650 A1 WO2016155650 A1 WO 2016155650A1 CN 2016078105 W CN2016078105 W CN 2016078105W WO 2016155650 A1 WO2016155650 A1 WO 2016155650A1
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factor viii
moisture content
model
human factor
sample
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臧恒昌
庞广礼
仲立军
王斐
姜玮
李连
张惠
李�灿
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山东大学
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light

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  • Human coagulation factor VIII (FVIII) is an important coagulation factor of the endogenous coagulation pathway, which is involved in the activation of coagulation factor X and plays an irreplaceable role in normal coagulation.
  • the hereditary deficiency of human factor VIII will lead to hemophilia A, so regular intravenous infusion of human factor VIII preparation is the primary treatment for hemophilia A.
  • human factor VIII preparations in China.
  • the human blood coagulation factor VIII preparations currently on the market are freeze-dried preparations obtained by lyophilization, and moisture is an important parameter for ensuring product quality, and its content and form have a great influence on the structure and function of human factor VIII. Directly related to the stability of human factor VIII preparation products.
  • the method for determining the moisture content is generally a complicated, time-consuming, labor-intensive and destructive chemical method, and the full inspection of the preparation product cannot be achieved to ensure the safety and effectiveness of the medicine flowing into the market.
  • the present invention provides a method for rapidly determining the moisture content in the human blood coagulation factor VIII product, which is simple, rapid, green and environmentally friendly, and is separated by Xilin.
  • the bottle can be tested for moisture content without destroying the sample, and all inspections of the manufactured drugs can be achieved.
  • the present invention is achieved in the following manner:
  • a method for rapidly determining the moisture content of a human factor VIII product comprising the following steps:
  • the preferred freeze-drying time in step (1) is from 12 h to 48 h, the freeze-drying temperature is -20 ° C, the preferred analytical drying temperature is 32 ° C, the vacuum is 10 Pa, and the drying time is from 5 to 24 h.
  • the near-infrared spectrometer is an Antaris II Fourier transform near-infrared spectrometer.
  • the acquisition conditions of the near-infrared spectrum are: the spectral resolution is 8 cm -1 , the number of scans is 32, and the spectral range is 10000-4000 cm -1 .
  • the samples were collected for 3 spectra and averaged, and the samples packed in the vials were directly subjected to spectral acquisition.
  • the sample set partitioning method used in the step (3) is a sample set partitioning based on joint xy distance (SPXY) method, and the correction set and the verification set are divided according to the ratio of 2.0-2.2:1, and finally 59 calibration set samples and 29 validation set samples.
  • SPXY joint xy distance
  • step (5) the lyophilized sample is taken, the near-infrared spectrum is collected according to the conditions in the step (2), and the obtained near-infrared spectrum is fitted to the optimal PLS quantitative analysis model to obtain a human factor VIII preparation.
  • the moisture content of the product is obtained.
  • the method is simple, rapid, non-destructive, green and environmentally friendly, and can accurately and quickly determine the moisture content of the finished product without destroying the packaging and the sample, can realize the real-time release of the product, guarantee the product quality, improve the safety and effectiveness of the medicine. Provide important support.
  • Figure 3 is a graph showing the results of a mathematical model obtained by the present invention.
  • FVIII Preparation of lyophilized samples of different moisture content
  • Some samples were lyophilized for more than 24 hours, and analyzed and dried in a vacuum oven at a temperature of 32 ° C and a vacuum of 10 Pa for 5-24 hours.
  • the spectral scanning range is 10000cm -1 -4000cm -1
  • the resolution is 8cm -1 .
  • the number of spectral scans was 32, and 3 spectra were acquired for each sample.
  • the absorption intensity of the near-infrared diffuse reflectance spectrum is set to Log (1/R).
  • Pretreatment method R RMSECV (%) RMSEP (%) LVs No treatment 0.8276 0.7154 0.5339 5 SG 15 point smoothing 0.8246 0.7227 0.5370 5 SNV 0.8608 0.6156 0.5174 6 MSC 0.7906 0.8256 0.5885 5 First derivative SG15 point smoothing 0.8295 0.6689 0.5523 3 SNV+ first derivative SG 15 point smoothing 0.9033 0.6138 0.4593 5 MSC+ first derivative SG 15 point smoothing 0.9022 0.6149 0.4616 5
  • the modeling variables were optimized by using UVE, iPLS, CARS and other variable selection methods, and compared with the full spectrum modeling results. The results are shown in Table 3.
  • the optimal variable selection method is the iPLS method.
  • the selected bands for modeling are 7471-7660 cm -1 , 6121-6310 cm -1 , 4964-5153 cm -1 and 4000-4189 cm -1 . .
  • the predicted moisture content in the model is 0.9996%-5.3031%, and the RMSEP value is 0.4514%, which can meet the needs of rapid inspection and release when the product leaves the factory.
  • the analysis time is shortened to ⁇ 1 minute, and the moisture content can be realized. Fast and efficient measurement enables full inspection of products to be shipped.

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  • Spectroscopy & Molecular Physics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

一种快速测定人凝血因子VIII成品中水分含量的方法，包括如下步骤：(1)制备不同水分含量的人凝血因子VIII制剂产品；(2)采用近红外光谱仪直接进行近红外光谱的采集，对样品中的水分含量进行测定；(3)对不同水分含量的样品集进行划分，得到用于建立模型的校正集和用于验证模型预测能力的验证集；(4)对比不同预处理方法及建模波段下模型的评价参数，得到最佳的预处理方法及建模波段，建立用于水分含量测定的PLS定量分析模型；(5)取待测样品，进行近红外光谱的采集，将得到的光谱对模型进行拟合，得到人凝血因子VIII制剂产品中水分含量值。该方法简单易行、快速无损、绿色环保，特别适合冻干型人凝血因子VIII冻干成品中的水分快速测定。

Description

一种快速测定人凝血因子VIII成品中水分含量的方法 技术领域
本发明涉及一种近红外光谱分析技术快速测定人凝血因子VIII成品中水分含量的方法。
背景技术
人凝血因子VIII(human coagulation factor VIII，FVIII)是内源性凝血途径的一种重要的凝血因子，参与凝血因子X的激活，在正常的凝血过程中发挥着无可替代的作用。人凝血因子VIII遗传性的缺乏将导致甲型血友病，因此定期静注人凝血因子VIII制剂是甲型血友病的主要的治疗手段。目前，由于原料来源的严重缺乏，加之生产工艺的限制，我国人凝血因子VIII制剂严重短缺。
目前市场上销售的人凝血因子VIII制剂均为经过冷冻干燥得到的冻干制剂，水分是确保产品质量的一个重要参数，它的含量和存在形式对人凝血因子VIII的结构和功能影响很大，直接关系人凝血因子VIII制剂产品的稳定性。现有技术中，水分含量的测定方法一般为操作复杂、耗时耗力且具有破坏性的化学方法，不能实现制剂产品的全检，以保证流入市场药品的安全性和有效性。
发明内容
为解决现有水分含量测定方法中费时费力、具有破坏性等问题，本发明提供了一种快速测定人凝血因子VIII成品中水分含量的方法，本方法简单快速、绿色环保，且在隔着西林瓶、不破坏样品的情况下进行样品水分含量的测定，可实现出厂药品的全部检验。
本发明是通过以下方式实现的：
一种快速测定人凝血因子VIII成品中水分含量的方法，包括步骤如下：
(1)对样品进行冷冻干燥和解析干燥，在不同的干燥时间或温度条件下制备得到不同水分含量的人凝血因子VIII制剂产品；
(2)将得到的不同水分含量的人凝血因子VIII制剂产品，采用近红外光谱仪直接进行近红外光谱的采集，采用卡尔费休水分测定法对各样品中的水分含量进行测定；
(3)采用SPXY方法对不同水分含量的样品集进行划分，得到用于建立模型的校正集和用于验证模型预测能力的验证集；
(4)对比不同预处理方法及建模波段下模型的评价参数，得到最佳的预处理方法及建模波段，建立用于水分含量测定的PLS定量分析模型；
(5)取冻干后的样品，进行近红外光谱的采集，将得到的样品光谱对模型进行拟合，得到人凝血因子VIII制剂产品中水分含量值。
上述方法中：
步骤(1)中优选的冷冻干燥时间为12h-48h，冷冻干燥温度为-20℃，优选的解析干燥的温度为32℃，真空度为10Pa，干燥时间为5-24h。
步骤(2)中近红外光谱仪为Antaris Ⅱ傅里叶变换近红外光谱仪，近红外光谱的采集条件为：光谱分辨率为8cm-1，扫描次数为32，光谱范围为10000-4000cm-1，每个样品采集3张光谱进行平均，将包装在西林瓶中的样品直接进行光谱的采集。
步骤(3)中采用的样品集划分方法为sample set partitioning based on joint xy distance(SPXY)法，根据2.0-2.2:1的比例进行校正集和验证集的划分，最终得到59个校正集样品和29个验证集样品。
步骤(4)中考察不同的预处理方法，预处理方法为SG 15点平滑、SNV、MSC、一阶导数SG15点平滑、SNV+一阶导数SG 15点平滑、或MSC+一阶导数SG 15点平滑，最终得到最佳的光谱预处理方法为SNV+一阶导数SG 15点平滑；对UVE、iPLS、CARS等变量选择方法进行比较，模型结果显示最佳的波段选择方法为iPLS法，选择的用于模型建立的近红外光谱波段为7471-7660cm-1,6121-6310cm-1,4964-5153cm-1和4000-4189cm-1。
步骤(5)中取冻干后的样品，按照步骤(2)中条件进行近红外光谱的采集，然后将得到的近红外光谱拟合建立的最佳PLS定量分析模型，得到人凝血因子VIII制剂产品中水分含量值。
本方法简单易行、快速无损、绿色环保，在不破坏包装和样品的情况下能准确快速测定成品中水分含量，能够实现产品的实时放行，对保证产品质量、提高药品的安全性和有效性提供重要的支撑。
附图说明
图1为本发明采集的人凝血因子VIII成品的漫反射近红外光谱；
图2为本发明经预处理后的光谱以及选择用于数学模型建立的光谱区间；
图3为本发明获得的数学模型结果图。
具体实施方式
下面结合实施例对本发明作进一步的说明。
实施例1
(1)不同水分含量FVIII冻干样品的制备：取FVIII冻干剂，每瓶加10mL注射用水溶解完全，置于-80℃超低温冰箱预冻2h以上，-20℃条件下冻干12h-48h不等，取冻干24h以上的部分样品，于温度为32℃、真空度为10Pa的真空干燥箱中解析干燥5-24h不等，得 到88个不同水分含量的冻干样品。
(2)采用Antaris Ⅱ傅里叶变换近红外光谱仪积分球漫反射分析模块进行近红外光谱的采集，仪器的工作参数为：光谱扫描范围为10000cm-1-4000cm-1，分辨率为8cm-1，光谱扫描次数为32，每个样品采集3张光谱。近红外漫反射光谱吸收强度设定为Log(1/R)。
(3)采用SPXY方法对样品集进行划分，获得校正集样品59个，验证集样品29个，具体的划分信息如表1所示。
表1样品集划分信息
样品集 样品数 范围(％) 均值(％) 标准偏差
校正集 59 0.9996-5.3031 2.8325 1.0376
验证集 29 1.1101-5.2047 2.9005 0.9860
(4)利用Matlab 2010a以及基于Matlab软件的PLS_Toolbox软件进行PLS模型的建立，为消除背景信息的干扰，对光谱进行预处理。在全光谱范围内分别考察了SG 15点平滑、SNV、MSC、一阶导数SG15点平滑、SNV+一阶导数SG 15点平滑、MSC+一阶导数SG 15点平滑对PLS模型结果的影响。利用百叶窗交互验证(venetian blinds cross validation)方法选择最佳的潜在变量数(LVs)。PLS模型的评价参数包括相关系数(R)，交互验证均方根误差(RMSECV)，预测均方根误差(RMSEP)。表2为不同预处理方法模型结果表，通过评价参数的比较，最佳的预处理方法为SNV+一阶导数SG 15点平滑，经过光谱的预处理后有效的消除了光谱的基线漂移，提高的光谱的分辨率，有利于有效信息的提取。
表2不同预处理方法建模结果
预处理方法 R RMSECV(％) RMSEP(％) LVs
无处理 0.8276 0.7154 0.5339 5
SG 15点平滑 0.8246 0.7227 0.5370 5
SNV 0.8608 0.6156 0.5174 6
MSC 0.7906 0.8256 0.5885 5
一阶导数SG15点平滑 0.8295 0.6689 0.5523 3
SNV+一阶导数SG 15点平滑 0.9033 0.6138 0.4593 5
MSC+一阶导数SG 15点平滑 0.9022 0.6149 0.4616 5
(5)为消除无关变量对PLS模型的影响，分别采用UVE、iPLS、CARS等变量选择方 法对建模变量进行优化，与全光谱建模结果进行比较，结果如表3所示。通过RMSECV和RMSEP值的比较，最佳的变量选择方法为iPLS法，选择的用于建模的波段为7471-7660cm-1,6121-6310cm-1,4964-5153cm-1和4000-4189cm-1。得到的模型的R＝0.9284，RMSECV＝0.4986％，RMSEP＝0.4514％，LVs＝7，参与PLS定量分析模型建立的变量数为200个。
表3不同变量选择方法建模结果
变量选择方法 R RMSECV(％) RMSEP(％) LVs 建模变量数
无选择 0.9033 0.6138 0.4593 5 1557
UVE 0.9203 0.4771 0.4626 7 270
iPLS 0.9284 0.4986 0.4514 7 200
CARS 0.9230 0.4020 0.5249 4 46
(6)建立的模型中得到的水分含量预测范围为0.9996％-5.3031％，RMSEP值为0.4514％，能够满足产品出厂时快速检验放行的需要，分析时间缩短为<1分钟，可实现水分含量的快速、有效的测定，能够实现待出厂产品的全检。
表4验证集样品真实值和预测值对比结果
编号 真实值(％) 测量值(％) 编号 真实值(％) 测量值(％)
2 1.1101 1.4377 46 2.7446 2.6473
4 1.6195 1.6531 48 2.7490 2.6196
7 1.7577 1.8069 49 2.7506 2.8374
10 1.8784 1.4693 51 2.8017 2.8437
11 1.9175 2.0672 55 2.8474 2.6612
19 2.1707 2.8929 57 3.1334 3.2553
22 2.3451 1.4556 60 3.2423 3.2750
27 2.4086 2.6751 62 3.5164 3.6902
29 2.4688 2.8319 67 3.5945 3.6834
36 2.5182 2.9940 72 4.3591 4.0007
37 2.5628 1.4905 74 4.3650 4.2238
40 2.5889 3.0404 76 4.5051 3.5795
41 2.6275 2.7926 80 4.9045 4.1053
42 2.7049 2.8627 86 5.2047 4.4235
44 2.7171 2.4293      
上面所述的实施例仅是对本发明的优选实施方式进行描述，并非对本发明的构思和保护范围进行限定，在不脱离本发明设计构思的前提下，本领域中普通工程技术人员对本发明的技术方案做出的各种变型和改进，均应落入本发明的保护范围。

Claims (9)

  1. 一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，包括步骤如下：
    (1)对样品进行冷冻干燥和解析干燥，在不同的干燥时间或温度条件下制备得到不同水分含量的人凝血因子VIII制剂产品；
    (2)将得到的不同水分含量的人凝血因子VIII制剂产品，采用近红外光谱仪直接进行近红外光谱的采集，采用卡尔费休水分测定法对各样品中的水分含量进行测定；
    (3)采用SPXY方法对不同水分含量的样品集进行划分，得到用于建立模型的校正集和用于验证模型预测能力的验证集；
    (4)对比不同预处理方法及建模波段下模型的评价参数，得到最佳的预处理方法及建模波段，利用数学处理软件建立用于水分含量测定的PLS定量分析模型；
    (5)取冻干后的样品，进行近红外光谱的采集，将得到的样品光谱对模型进行拟合，得到人凝血因子VIII制剂产品中水分含量值。
  2. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(1)中冷冻干燥时间为12h-48h，冷冻干燥温度为-20℃。
  3. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(1)中解析干燥的温度为32℃，真空度为10Pa，干燥时间为5-24h。
  4. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(2)中近红外光谱仪为AntarisⅡ傅里叶变换近红外光谱仪，近红外光谱的采集条件为：光谱分辨率为8cm-1，扫描次数为32，光谱范围为10000-4000cm-1，每个样品采集3张光谱进行平均，将包装在西林瓶中的样品直接进行光谱的采集。
  5. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(3)中划分得到59个校正集样品和29个验证集样品。
  6. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(4)中预处理方法为SG 15点平滑、SNV、MSC、一阶导数SG15点平滑、SNV+一阶导数SG 15点平滑、或MSC+一阶导数SG 15点平滑。
  7. 根据权利要求6所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(4)中预处理方法为SNV+一阶导数SG 15点平滑。
  8. 根据权利要求1所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，步骤(4)波段选择方法包括UVE、iPLS、CARS法。
  9. 根据权利要求8所述的一种快速测定人凝血因子VIII成品中水分含量的方法，其特征是，波段选择方法为iPLS波段选择方法，选择的建模波段为7471-7660cm-1,6121-6310cm-1, 4964-5153cm-1和4000-4189cm-1。
PCT/CN2016/078105 2015-03-31 2016-03-31 一种快速测定人凝血因子viii成品中水分含量的方法 WO2016155650A1 (zh)

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