Geng, Yuhao; (2023) Electrospun polymer fibers for advanced drug delivery systems. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes work aiming to develop polymer fibers giving a range of drug release profiles, including fast-release and sustained-release. Polymer fibers were fabricated using the electrospinning technology. Particular focus was applied to scaling up the process. A fast-release system was developed using poly(vinyl pyrrolidone) (PVP) fibers loaded with ketoprofen (Chapter 2). These PVP fibers comprise potential fast-dissolving drug delivery systems (DDSs) for use in the oral cavity. By changing the processing parameters and collector geometry it was possible to increase the throughput from 1 to 20 mL/h. The fibers all took the shape of cylinders and had smooth surfaces. They comprise amorphous solid dispersions of drug-in-polymer, with very high drug encapsulation efficiencies (essentially 100 %). With a low drug loading (9.09 % w/w), the electrospun materials could disintegrate quickly and accelerate the dissolution profile of ketoprofen under non-sink conditions representative of the oral cavity. However, at higher loadings (23.08 % w/w), this benefit is no longer realized, indicating that there is a maximum drug loading above which the dissolution-enhancing properties of the amorphous form and the hydrophilic PVP carrier cease to be effective. After storage under ambient conditions (19–21°C, relative humidity 30–40 %) for 4 weeks, the formulations remained amorphous, with no significant changes in their drug release properties. Very similar behaviour in terms of drug release and storage stability was seen regardless of the throughput rate used for fiber fabrication, showing the potential to rapidly produce large amounts of high-performing material. A second series of experiments (Chapter 3) also used PVP as the carrier matrix, loading nicotinamide as a model ingredient to make fibers with scaled-up needleless electrospinning. The flow rate could be elevated to 60 and 100 mL/h, and the formulation showed potential as a fast dissolving system. As comparisons, the same formulations were also manufactured with a spinning flow rate at 1 and 20 mL/h using bench-top and with-needle scaled-up electrospinning. Nicotinamide and the polymer were both amorphous in the fibers, and all the fibers showed an encapsulation efficiency at around 80 %. The NMR results indicated some chemical conversion from nicotinamide to nicotinic acid occurred during the process of dissolving the raw materials and processing into electrospun fibers, which led to a reduction in the encapsulation efficiency, and future studies are required to avoid this conversion. The low-loading formulations (9.09 % w/w) and high-loading formulations (23.08 % w/w) both showed fast release profiles under sink conditions. After aging under ambient conditions (19–21 °C, relative humidity 30–40 %) for 4 weeks, all formulations remained amorphous and still provided rapid release of the encapsulated drug. These experiments show that the needleless electrospinning has the potential to fabricate fibrous mats with high productivity. The third set of experiments (Chapter 4) was conducted with ethyl cellulose (EC) as the matrix polymer and captopril as a model drug, with the goal to fabricate electrospun fibers as sustained release gastro-retentive drug delivery systems. Bench-top electrospinning was carried out with a flow rate of 1mL/h, and the scaled-up method (with needle) used a flow rate of 20 mL/h. Both processes yielded EC-based fibers in the shape of cylinders and with smooth surfaces. The drug was distributed through the polymer in the amorphous state according to X-ray diffraction (XRD) and differential scanning calorimetry (DSC) results. The encapsulation efficiency of all the formulations is almost 100 %, and release studies in simulated gastric fluid indicated slower release profiles compared with a physical mixture of captopril and EC. The electrospun fibers with low-loading (9.09 % w/w) showed a slower release period than fibers with high-loading (23.08 % w/w). After aging under ambient conditions (19–21 °C, relative humidity 30–40 %) for 8 weeks, all the fibers remained amorphous and the release profiles had no significant changes compared with fresh fibers. However, there was a burst of release in all cases, which is not desirable in a sustained release system. In order to solve the problem of the initial “burst” release of the blend-electrospun fibers in Chapter 4, coaxial electrospinning was employed in Chapter 5. Here, core/shell fibers were prepared. The shell comprised EC with no drug, while captopril was encapsulated in the core blended with EC. Both bench-top electrospinning and scaled-up needle-based electrospinning were applied. All fibers were cylindrical in shape with a wrinkled surface, and confocal microscopy suggested them to have a core/shell structure. DSC and XRD results confirmed that the fibers were amorphous. The encapsulation efficiency is nearly 100 %. All the fibers exhibited sustained release profiles; however, the low-loading formulations (3.23 % w/w drug) showed very slow release over 24 h. Considering the high-loading formulations (9.09 % w/w), the fibers manufactured with scaled-up electrospinning showed slower release than those fabricated with bench-top electrospinning. This is thought to be a result of the difference in fiber diameters, as bench-top-electrospun fibers had a mean diameter of ca. 0.62–0.64 μm, while the average diameter for fibers prepared by scaled-up electrospinning was ca. 1.32–1.60 μm. After storage under ambient conditions (19–21 °C, relative humidity 30–40 %) for 8 weeks, all the fibers remained amorphous and there were no significant changes in the release profiles compared with fresh fibers. The experiment showed the potential of coaxial-electrospinning in fabricating a sustained release gastro-retentive system for captopril, and scaled-up electrospinning not only improved manufacturing productivity but also provided a slower release profile by increasing the fiber diameter. Overall, the electrospinning showed the potential to fabricate fibers for purposes of both fast release and sustained release of encapsulated active pharmaceutical ingredients (APIs), based on the hydrophilic and hydrophobic polymers that were respectively used as the polymer matrices. Scaled-up electrospinning technology could be applied to increase productivity, with no loss of functional performance. By means of needle-based scaled-up electrospinning and needleless electrospinning, the spinning flow rate could be raised to 20 mL/h and 100 mL/h, respectively, while the bench-top electrospinning only used a flow rate of 1–2 mL/h. For sustained release formulations, coaxial-electrospinning was valuable as a technology to solve the problem of the initial “burst” of release that was seen in the release profiles of blend-electrospun fibers. It could further lead to release being maintained over a longer period of time. The combination of coaxial-electrospinning and needle-based scaled-up electrospinning has potential to manufacture fibers for improved sustained drug release with the additional benefit of increased productivity.

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