Abstract
The current study aimed at exploring the effect of non-uniform drug distribution and
diffusivity in drug eluting stent (DES) coating and to use this strategy to optimize the
drug release profile. In this study, the film casting method was assessed and optimized
to fabricate monolayer films down to 3 μm thickness. Through the adsorption between
the ultra-thin films, a multilayer film with a total thickness of approximately 10 μm
stacked by three layers was fabricated. Since the thickness of the multilayer film is
similar to the drug-loaded coating of commercial stents, the drug release based on this
multilayer film has the potential for practical applications. By casting and loading the
three-layer films separately, a customizable multilayer Poly (lactic acid) (PLA) film
was fabricated to explore the effect of the distribution of different drugs and Poly
(ethylene glycol) (PEG) on the drug release kinetics. In addition to investigating the
release profiles of different configurations of multilayer film, scanning electron
microscopy was applied to measure the film thickness and surface morphology, optical coherence tomography was used to observe the cross section of multilayer film, differential scanning calorimetry was applied to further investigate the causes of
changes in release behavior, and a biological characterization using human
keratinocyte was also performed to assess the biocompatibility. To ensure the accuracy of the release test, four generations of sealing devices that can
seal the multilayer film were designed. The sealing device (G4-seal ring), which was
used in the final drug release test, was examined in the sealing test based on the
hydrophilic Ponceau 4R-loaded multilayer film to ensure that the release medium did
not directly contact the middle layer or inner layer within 25 days. The G4-seal ring
has the advantages of easy assembly, stable sealing effect, low production cost, and it
can be applied to other polymer film-based drug release tests. Turmeric was used as a model drug in this thesis study. In the turmeric release test, it
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was found that the initial burst release of the samples with all three layers containing
5% PEG was inhibited, suggesting that a small amount of PEG could limit the drug
release. In addition, amongst the 11 configurations, the configuration with two layers
of release barrier (5% PEG in PLA) and all drugs distributed in the inner layer
(sample-10) provided the lowest burst release and the highest n value of the
Korsmeyer-Peppas model, which means the configuration of sample-10 significantly
improved the release kinetics of turmeric. Besides this, the configuration with a
single-layer release barrier (5% PEG in PLA) and gradient distribution of the drug in
the middle and inner layers (sample-9) provides n values very close to sample-10. At
the same time, the turmeric release of sample-9 between day 1 and day 10 was greater
than sample-2 (uniform drug distribution and no PEG content). In addition, this study
also summarized information about the effect of drug and PEG distribution on the
drug release behavior of multilayer films from the results of the turmeric release test. By applying the configuration of sample-9 and -10 to the everolimus (EVR) release
test, it was known that the release barrier significantly inhibited the release of EVR
within 25 days. The results of cell experiments based on HaCaT cells showed that the drug release
medium from EVR release rate-limited samples reduced the negative impact of EVR
on cell viability (no significant difference from untreated group-Cell only control), whereas the release medium from EVR uniformly distributed sample-ND resulted in a
significant drop in cell viability. The results of this study enhance our understanding about drug release mechanism in
a multilayer system, and also demonstrate that non-uniform drug distribution and
diffusivity in drug-loaded coating can effectively improve drug release profile and
biocompatibility of drug-loaded coating.