Advanced Engineering of Contact Lens Coatings using Electrohydrodynamic Atomization

While the eye presents numerous opportunities for drug delivery (DD); there are many challenges met by conventional methods. Despite the exponential growth in research to overcome these downfalls and achieve sustained and controlled DD, the anatomical characteristics of the eye still pose formulation challenges. The research presented in this thesis utilises Electrohydrodynamic Atomization (EHDA) to engineer novel coatings for ocular contact lenses. EDHA was selected to develop coatings for the delivery of timolol maleate (TM); with the intention of achieving sustained drug release for treatment of glaucoma. The work presented here is a proof-of-concept; showing the versatility of a promising technique by applying it to a DD remit within which EHDA has not yet been fully exploited: Ocular Drug Delivery (ODD). The first step was to identify a suitable polymeric matrix to act as the vehicle/carrier and see the effects of different polymers on the in vitro release of TM and ex vivo TM permeation. Hereafter, based on the results of this work, 4 different PEs were incorporated to attempt to enhance TM release and permeation through the cornea. Further modification of the formulations saw the effect of integrating chitosan on the release of TM from the electrically atomised coatings. Characterisation of the atomised coatings at each stage demonstrated highly stable matrices, which possessed extremely advantageous morphologies and sizes (within the nanometre range). All coatings also demonstrated adequate to high encapsulation efficiencies (EEs) (>64%) with the highest EE being 99.7%. In vitro release (i.e. cumulative percentage release) steadily increased upon introduction of additives to the base polymeric formulations yielding different release profiles; ranging from biphasic profiles to triphasic profiles. Ex vivo analysis and biological compatibility testing also presented promising results. The use of EHDA has not yet been explored in depth within the ocular research remit. It has shown great potential in the work presented here; engineering on demand lens coatings capable of sustaining both TM release and TM permeation

Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link

Quality by design micro-engineering optimisation of NSAID-loaded electrospun fibrous patches

The purpose of this study was to apply the Quality by Design (QbD) approach to the electrospinning of fibres loaded with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin (INDO) and diclofenac sodium (DICLO). A Quality Target Product Profile (QTPP) was made, and risk assessments (preliminary hazard analysis) were conducted to identify the impact of material attributes and process parameters on the critical quality attributes (CQAs) of the fibres. A full factorial design of experiments (DoE) of 20 runs was built, which was used to carry out experiments. The following factors were assessed: Drugs, voltage, flow rate, and the distance between the processing needle and collector. Release studies exhibited INDO fibres had greater total release of active drug compared to DICLO fibres. Voltage and distance were found to be the most significant factors of the experiment. Multivariate statistical analytical software helped to build six feasible design spaces and two flexible, universal design spaces for both drugs, at distances of 5 cm and 12.5 cm, along with a flexible control strategy. The current findings and their analysis confirm that QbD is a viable and invaluable tool to enhance product and process understanding of electrospinning for the assurance of high-quality fibres

Engineering and development of chitosan-based nanocoatings for ocular contact lenses

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.The research manuscript reports on Electrohydrodynamic Atomisation (EHDA) to engineer on-demand novel coatings for ocular contact lenses. A formulation approach was adopted to modulate the release of timolol maleate (TM) using chitosan and borneol. Polymers polyvinylpyrrolidone (PVP) and poly (N-isopropylacrylamide) (PNIPAM) were utilised to encapsulate TM and were electrically atomised to produce optimised, stationary contact lens coatings. The particle and fibre diameter, thermal stability, material compatibility of the formed coatings along with their in vitro release-modulating effect and ocular tolerability were investigated. The results demonstrated highly stable nano-matrices with advantageous morphology and size. All formulations yielded coatings with high TM encapsulation (>88%); with excellent ocular biocompatibility. The coatings presented biphasic and triphasic release profiles; depending on composition. Kinetic modelling revealed a noticeable effect of chitosan; the higher the concentration, the more the release of TM due to chitosan swelling; with the release mechanism changing from Fickian diffusion (1% w/v; n = 0.5) to non-Fickian (5% w/v, 0.45 < n < 0.89). The use of EHDA has not yet been explored in depth within the ocular research remit; engineering on demand lens coatings capable of sustaining TM release. This is likely to offer an alternative dosage form for management of glaucoma with particular emphasis on improving poor patient compliance

Assessing the ex vivo permeation behaviour of functionalised contact lens coatings engineered using an electrohydrodynamic technique

In vitro testing alone is no longer considered sufficient evidence presented solely with respect to drug release and permeation testing. These studies are thought to be more reliable and representative when using tissue or animal models; as opposed to synthetic membranes. The release of anti-glaucoma drug timolol maleate from electrically atomised coatings was assessed here using freshly excised bovine corneal tissue. Electrohydrodynamic processing was utilised to engineer functionalised fibrous polyvinylpyrrolidone-Poly (N-isopropylacrylamide) coatings on the outer side of commercial silicone contact lenses. Benzalkonium chloride, ethylenediaminetetraacetic acid, Brij® 78 and borneol were employed as permeation enhancers to see their effect on ex vivo permeation of timolol maleate through the cornea. Formulations containing permeation enhancers showed a vast improvement with respect to cumulative amount of drug permeating through the cornea as shown by a six fold decrease in lag time compared to enhancer-free formulations. Most drug delivery systems require the drug to pass or permeate through a tissue or biological membrane. This study has shown that to fully appreciate and understand how a novel drug delivery system will behave not only within the device but with the external environment or tissue, it is imperative to have in vitro and ex vivo data in conjunction

Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Despite exponential growth in research relating to sustained and controlled ocular drug delivery; anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15 μL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24 hours (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p < 0.05) in TM release dependant on permeation enhancer

Electrospinning/electrospraying coatings for metal microneedles: a design of experiments (DOE) and quality by design (QbD) approach

The research presented here shows QbD implementation for the optimisation of the key process parameters in electrohydrodynamic atomisation (EHDA). Here, the electrosprayed nanoparticles and electrospun fibers consisting of a polymeric matrix and dye. Eight formulations were assessed consisting of 5% w/v of polycaprolactone (PCL) in dichloromethane (DCM) and 5% w/v polyvinylpyrrolidone (PVP) in ethanol. A full factorial DOE was used to assess the various parameters (applied voltage, deposition distance, flow rate). Further particle and fiber analysis using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), particle/fiber size distribution. In addition to this in vitro release studied were carried out using fluorescein and Rhodamine B as model dyes and in vitro permeation studies were applied. The results show a significant difference in the morphology of resultant structures as well as a more rapid release profile for the PVP particles and fibers in comparison to the sustained release profiles found with PCL. In vitro drug release studies showed 100% drug release after 7 days for PCL particles and showed 100% drug release within 120 min for PVP particles. The release kinetics and the permeation study showed that the MN successfully pierced the membrane and the electrospun MN coating released a large amount of the loaded drug within 6 h. This study has demonstrated the capability of these robust MNs to encapsulate a diverse range drugs within a polymeric matrix giving rise to the potential of developed personalised medical devices