Doxorubicin eluting beads—2: methods for evaluating drug elution and in-vitro:in-vivo correlation

Abstract

DC Bead 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.

Drug-Eluting Beads Loaded with Antiangiogenic Agents for Chemoembolization: In Vitro Sunitinib Loading and Release and In Vivo Pharmacokinetics in an Animal Model

“…The low 24 h value (p.o.) of 7 ng/ml was determined in an animal whose plasma levels accounted only for 4 ng/ml at 6 h. The bead consists of poly(vinyl alcohol)-based hydrogel linked to sulfonate groups, resulting in a negatively charged structure (28,29) that loads the protonated sunitinib with good performance. In accordance with Lewis' investigations, which did not show a significant difference in the loading kinetics for the smallest tested bead size ranges of 100 to 500 µm (28), the f 2 factor comparison revealed similar loading curves for the tested bead sizes.…”

“…In the absence of salts, negligible drug elution occurs (29,31), as observed during eight-week extraction assays in 5% glucose, which served as an isotonic storage medium in the syringes for the preclinical studies.…”

Sunitinib-eluting beads for chemoembolization: Methods for in vitro evaluation of drug release

“…The influx of small cations (Biondi et al, 2013;Liu et al, 2001) from biological fluids causes immediate release of the positively charged drug from the negatively charged sphere matrix. However so far, in vitro 60 dissolution methods resulting in slow drug release have been employed and validated for simulation of the in vivo environment, as the blood flow in embolized vessels is supposed to be reduced (Cheung et al, 2004;Gonzalez et al, 2008;Lewis et al, 2006). Among them, the Tapparatus (Gonzalez et al, 2008) and incubation of drug-eluting beads in vials (Biondi et al, 2013) led to differing diffusion mechanisms for the currently used drugs doxorubicin and 65 irinotecan.…”

“…Loading of sunitinib into DC Beads DC Bead microspheres (Biocompatibles Ltd., Farnham, UK) consist of a poly(vinyl alcohol)-based hydrogel whose crosslinker contains sulfonate groups, bearing an overall negatively charged structure (Gonzalez et al, 2008;Lewis et al, 2007). The protonation of the tertiary amine of the anti-angiogenic drug, sunitinib and consequent incubation with the concentrated spheres 80 results in high capacity of sunitinib loading into the spheres by ionic interaction (Denys et al, 07.06.2012;Fuchs et al, 2014).…”

“…This approach is commonly used to compare the performance of two products (USP36-NF31, 2013). The release profiles were also fitted into different kinetic 130 equations (zero order, first order, Higuchi, Peppas, and Boyd (Boyd et al, 1947;Chretien et al, 2004;Gonzalez et al, 2008;Reichenberg, 1953;Taylor et al, 2007)) to determine the governing release mechanism (Table 1).…”