Doxorubicin eluting beads -: 2:: methods for evaluating drug elution and in-vitro:in-vivo correlation
Doxorubicin eluting beads -: 2:: methods for evaluating drug elution and in-vitro:in-vivo correlation
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DOI：
10.1007/s10856-006-0040-y
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发表时间：
2008-02-01
影响因子：
3.7
通讯作者：
Lewis, Andrew L.
中科院分区：
文献类型：
--
作者：
Gonzalez, M. Victoria;Tang, Yiqing;Lewis, Andrew L.
DC Bead （TM）是一种磺酸修饰的pva基微球栓塞剂，被批准用于治疗高血管肿瘤和动静脉畸形。这些小珠先前已被证明能通过离子交换机制积极地隔离带相反电荷的药物，如盐酸阿霉素（dox）。为了表征药物洗脱珠（DEB）的释放动力学并预测其体内行为，采用了两种洗脱方法。第一个是USP溶出法II型仪器的应用，可以在不到4小时的时间内研究负载DC珠的完全洗脱，允许在不同产品和配方之间进行相对快速的比较。利用该方法获得的释放数据符合一级动力学（R-2 > 0.998），洗脱常数随着暴露于洗脱介质的珠粒总表面积的增加而增加。扩散系数采用菲克氏扩散模型计算，该模型预测生理条件下的缓慢洗脱速率。第二种方法涉及使用T-Apparatus，其中药物在静态环境中经历扩散元素。这种方法是为了更接近栓塞过程中的体内情况而开发的。使用缓释模型预测所有尺寸范围内半衰期超过1,500 h的DC Bead的dox缓释。在经动脉化疗栓塞（TACE）过程中，T-Apparatus的释放数据与使用负载dox的DC Bead治疗的患者获得的药代动力学数据之间存在很强的线性关系。这些数据表明，栓塞后24小时的体外-体内相关性（IVIVC）为a级。开发的两个系统都是自动化的，所有样品的重现性都很好，证明了这些洗脱技术对产品开发和比较测试的有用性。
DC Bead (TM) is a sulfonate-modified, PVA-based microspherical embolisation agent approved for the treatment of hypervascular tumours and arterio-venous malformations. The beads have previously been shown to actively sequester oppositely charged drugs, such as doxorubicin hydrochloride (dox) by an ion-exchange mechanism. In order to characterise the release kinetics and predict the in vivo behaviour of drug eluting beads (DEB), two elution methods were utilised. The first, an application of the USP dissolution method Type II - Apparatus, enables study of the complete elution of loaded DC Bead in less than 4 h, allowing relatively rapid comparison to be made between different products and formulations. Release data obtained using this method were fitted to first order kinetics (R-2 > 0.998) and the elution constants shown to increase with the total surface area of the beads exposed to the elution medium. Diffusion coefficients were calculated adopting the Fickian diffusion model, which predicted slow elution rates under physiological conditions. The second method involved the use of a T-Apparatus where the drug experiences an element of diffusion through a static environment. This method was developed to resemble the in vivo situation in embolisation procedures more closely. Slow release of dox from DC Bead with half-lives over 1,500 h were predicted for all size ranges using a slow release model. A strong linear relationship was found between the release data from T-Apparatus and pharmacokinetic data obtained from patients treated with DC Bead loaded with dox in transarterial chemoembolisation (TACE) procedures. These data indicated a Level A in vitro-in vivo correlation (IVIVC) for the first 24 h post embolisation. Both systems developed were automated and good reproducibility was obtained for all samples, demonstrating the usefulness of these elution techniques for product development and comparative testing.