Ali A. Al-Kinani

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

Graphical abstract Figure. No Caption available. Abstract Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye‐drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano‐coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio‐interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio‐surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano‐fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano‐structured coatings (for all formulations) were <200 nm in diameter. In vitro studies show coatings to exhibit biphasic release profiles; an initial burst release followed by sustained release; with TM‐loaded PNIPAM coating releasing most drug after 24 h (89.8%). Kinetic modelling (Higuchi, Korsmeyer‐Peppas) was indicative of quasi‐Fickian diffusion whilst biological evaluation demonstrates adequate ocular tolerability. Results from permeation studies indicate coated lenses are ideal to reduce dosing regimen, which in turn will reduce systemic drug absorption. Florescent microscopy demonstrated probe and probe embedded coating behaviour from lens surface in vitro. The multiple lens surface coating method demonstrates sustained drug release yielding promising results; suggesting both novel device and method to enhance drug activity at the eyes surface which will reduce formulation drainage.

Approaches in topical ocular drug delivery and developments in the use of contact lenses as drug-delivery devices

Drug-delivery approaches have diversified over the last two decades with the emergence of nanotechnologies, smart polymeric systems and multimodal functionalities. The intended target for specific treatment of disease is the key defining developing parameter. One such area which has undergone significant advancements relates to ocular delivery. This has been expedited by the development of material advancement, mechanistic concepts and through the deployment of advanced process technologies. This review will focus on the developments within lens-based drug delivery while touching on conventional and current methods of topical ocular drug delivery. A summary table will provide quick reference to note the key findings in this area. In addition, the review also elucidates current theranostic and diagnostic approaches based on ocular lenses.

Ophthalmic gels: Past, present and future

Abstract Aqueous gels formulated using hydrophilic polymers (hydrogels) along with those based on stimuli responsive polymers (in situ gelling or gel forming systems) continue to attract increasing interest for various eye health‐related applications. They allow the incorporation of a variety of ophthalmic pharmaceuticals to achieve therapeutic levels of drugs and bioactives at target ocular sites. The integration of sophisticated drug delivery technologies such as nanotechnology‐based ones with intelligent and environment responsive systems can extend current treatment duration to provide more clinically relevant time courses (weeks and months instead of hours and days) which will inevitably reduce dose frequency, increase patient compliance and improve clinical outcomes. Novel applications and design of contact lenses and intracanalicular delivery devices along with the move towards integrating gels into various drug delivery devices like intraocular pumps, injections and implants has the potential to reduce comorbidities caused by glaucoma, corneal keratopathy, cataract, diabetic retinopathies and age‐related macular degeneration. This review describes ophthalmic gelling systems with emphasis on mechanism of gel formation and application in ophthalmology. It provides a critical appraisal of the techniques and methods used in the characterization of ophthalmic preformed gels and in situ gelling systems along with a thorough insight into the safety and biocompatibility of these systems. Newly developed ophthalmic gels, hydrogels, preformed gels and in situ gelling systems including the latest in the area of stimuli responsive gels, molecularly imprinted gels, nanogels, 3D printed hydrogels; 3D printed devices comprising ophthalmic gels are covered. Finally, new applications of gels in the production of artificial corneas, corneal wound healing and hydrogel contact lenses are described. Graphical abstract Figure. No Caption available.

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

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 15μL/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 24h (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.

Nanotechnology in ophthalmic drug delivery

Conventional ophthalmic dosage forms are easy to prepare, administer, and their manufacture cost is relatively low. However, aqueous eye solutions suffer from very short contact time with the ocular surface and fast nasolacrimal drainage, both leading to poor bioavailability of the drug. Ointments have visibility and patient acceptably problems whereas suspensions often give rise to unpredictable and variable ocular bioavailability. To address the shortfalls of conventional ophthalmic dosage forms, nanotechnology-based systems have been investigated and some of which have been developed into marketed product. The present chapter overviews the emerging role of nanotechnology in ophthalmic drug delivery with emphasis on what has been patented over the past decade.

Fatty Acid Based Microemulsions to Combat Ophthalmia Neonatorum Caused by Neisseria gonorrhoeae and Staphylococcus aureus

The bacterial species Neisseria gonorrhoeae (N. gonorrhoeae) and Staphylococcus aureus (S. aureus) are amongst the main microorganisms that cause ophthalmia neonatorum. The current treatment involves the use of various antibiotics such as ciprofloxacin, cephalosporin, ceftriaxone and cefotaxime. However, this treatment strategy is becoming more ineffective due to the antibiotic resistance in N. gonorrhoeae. The current study explores the potential use of fatty acid based microemulsions (ME) to prevent N. gonorrhoeae and S. aureus infections in new-borns’ eyes without harmful side effects such as corneal or conjunctiva irritation. Pseudo-ternary phase diagrams were constructed to evaluate microemulsion regions and six different α-linolenic acid based microemulsions were prepared. The prepared formulations were characterized for α-linolenic acid content, size, transparency, zeta potential, Polarized light Microscopy, antimicrobial activity and ex vivo ocular toxicity. The mean droplet size of the ME formulations was in the range of 190.4 to 350.5 nm and polydispersity index (PDI) values were in the range of 0.102 to 0.561. All formulations were found stable upon storage for at least 8 weeks. In addition, self-diffusion coefficients determined by nuclear magnetic resonance (NMR) reflected that the diffusability of water increased at higher than 30% w/w water, while that of fatty acids and surfactants was in reverse. The antimicrobial efficacy of microemulsions was determined against N. gonorrhoeae and S. aureus. It was concluded that all microemulsions have strong antimicrobial effects against N. gonorrhoeae and S. aureus. Finally, bovine corneal opacity permeability (BCOP) and hen’s egg chorioallantoic (HET-CAM) tests results showed that all microemulsion formulations were not strong ocular irritants.