Abstract:
The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.
Keywords
Controlled release; diffusion; dissolution; dissolution rate; drug-delivery systems; in vitro models; mathematical model; microspheres
Citation: Emelie Ahnfelt, Erik Sjogren, Per Hansson, Hans Lennernas In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System http://dx.doi.org/10.1016/j.xphs.2016.08.011
Received: 1 July 2016, Revised: 8 August 2016, Accepted: 15 August 2016, Available online: 20 September 2016
Copyright: © 2016 American Pharmacists Association ®. Published by Elsevier Inc. All rights reserved.
Conclusion
In conclusion, smaller beads (70-150 μm) have up to twice the release rates of larger beads (100-300 and 300-500 μm), indicating the crucial role of the available total surface area for drug release. The temperature-dependent in vitro release demonstrated the impact of viscosity and diffusion constant changes. Buffer strengths of 10 mM decreased the released amount (Amax) of DOX with 70%-80% compared 100 mM. This is explainable, to some extent, by the corresponding decrease of positively charged ions. The combination of the 6-mm SR and 10-15 mL release medium described the in vivo release most accurately. The in vitro release of DOX was not influenced by pH, which indicates that the pH in the tumor microenvironment would not much affect the drug release of DOX from the beads in vivo. However, the influence of electrolytes on the in vivo release remains to be investigated. The release mechanism in the free-flowing method was film control, which was confirmed by the positive correlation between release rate and stirring rate for all bead sizes. The theoretical release modeling also suggested that the release of DOX from the beads was influenced by DOX-DOX aggregates, DOX-PVA interactions, and the equilibrium between protonated and deprotonated DOX. In addition, the available volume of release medium, potentially affecting the hydrodynamics and diffusion at the target site, may have had a greater impact on the release of DOX than that of the buffer strength. In future work, we intend to implement a thermodynamic model with a model for the release kinetics. This thermodynamic model will include charge regulation effects and aggregation in the solution, as well as the actual volume change of the beads.
Acknowledgments
Financial support was provided by the Swedish Research Council, grant number 521-2011-373. The analysis of the sulfur concentration was kindly performed by Jean Pettersson, Department of Chemistry, Uppsala University.
