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NANO CONGRESS 2019 In vitro studies of the release of doxorubicin and other amphiphilic drugs from microgels: Improved mechanistic understanding - Per Hansson-Uppsala University

Per Hansson

Abstract The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by2 miniaturized in vitro methods: free-�?owing 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-�?owing method. There was no difference between a pH of 6.3 or 7.4 on their lease rate, implying that the slightly acidic tum or 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 in�?uence 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 theoreticalmodeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS. Introduction In vitro investigations of drug release from drug-delivery systems (DDS) are of importance throughout the drug innovation and development process.1However, no standardized in vitro method exists for parenteral systems, and as a consequence, there is adversity of in vitro methods. The in vitro release rate of doxorubicin (DOX) from the microsphere DDS, DC Bead, has been investigated in paddle, sample and separate, �?ow through, and T-cell methods. These in vitro methods use relatively large amounts of DDS (1 mL) and release medium (200-900 ml). Miniaturized in vitro methods reduce the amounts of DDS sample, release medium and waste for example, to 20-65mL (DDS sample) and 10-20 mL (release medium). Another advantage of the miniaturized method is that a low volume of release medium may be more relevant to the in vivo site in hydrodynamic and diffusion properties.In this report, the in vitro release of DOX from the beads was tested in 2 miniaturized methods. The beads were loaded with DOX, a cytotoxic agent that is used in palliative treatment of intermediate-stage hepatocellular carcinoma. DOX has a molecular mass of 543.52 g/mol and a LogD7.5of2.42. The pK as of DOX are 7.34, 8.46, and 9.46, and the compound exists as both a deprotonated and protonated monovalent cation at physiological conditions. The beads consist of polyvinyl alcohol (PVA) with integrated, negatively charged 2-acrylamido-2-methylpropanesulfonate (AMPS) units. Ion exchange has been proposed as the mechanism for loading and release of protonated DOX from the AMPS sulfonic acid groups. The beads are no biodegradable, and the intrahepatic administration leads to a local drug delivery in combination with a full and permanent embolization of the treated hepatic arteries. In the clinic, the beads are delivered by radiological image guidance with anon ionic contrast medium, such as Omnipaque. The main objective of this study was to determine the mechanism(s) and release rate of DOX from the beads. Second, we investigated the effects of factors such as temperature, stir-ring rates, buffer strength, pH, and volume of release medium on the in vitro release rate. Third, selected in vitro release profileswere compared to an in vivo DOX-release data set. Finally, the release mechanism(s) were investigated with theoretical modeling. Experimental Design Am Diss profiler (pION) was used to determine the in vitro DOX release from the beads during various conditions. The drug concentration in the medium was determined as the area under the concentration wavelength curve of the second derivate spectrum at an interval of 553 to 572 nm. The application of the second derivate spectrum reduces the background turbidity, thereby enhancing peaks and reducing baseline shifting.21, 22Each channel was individually calibrated with the stock solutions against a standard curve. All release studies were per-formed under sink conditions (amount of DOX