Hydrogel-based ocular drug delivery systems: Emerging fabrication strategies, applications, and bench-to-bedside manufacturing considerations

Abstract

The physiological barriers of the eye pose challenges to the delivery of the array of therapeutics for the effective medication of ocular diseases as well as patient compliance. While the innovations in drug encapsulation and release mechanisms, biocompatibility, and treatment duration have become highly sophisticated, the challenge of widespread application of hydrogel formulations in the clinic is still apparent. This article reviews the latest hydrogel formulations and their associated chemistries for use in ocular therapies, spanning from external anterior to internal posterior regions of the eye in order to evaluate the state of recent research. This article discusses the utility of hydrogels in soft contact lens, wound dressings, intraocular lens, vitreous substitutes, vitreous drug release hydrogels, and cell-based therapies for regeneration. Additional focus is placed on the pre-formulation, formulation, and manufacturing considerations of the hydrogels based on individual components (polymer chains, linkers, and therapeutics), final hydrogel product, and required preparations for clinical/commercial applications, respectively.

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

“…Hydrogels are materials that consist of 3D cross-linked networks with 50–90% by weight of water, and do not flow upon inversion [ 139 ]. Gels have been used as wound dressings, vitreous substitutes and regenerative medicine [ 140 ]. Polymers commonly used in these systems include PLGA, PEG, poly(vinylpyrrolidone) (PVP), hyaluronic acid or hyaluronan (HA), poly(acrylamide) and collagen [ 141 ], as well as natural polymers, such as chitosan, xanthan gum, guar gum and carrageenan [ 142 ].…”

“…The temperature-induced change is governed by the balance between hydrophobic and hydrophilic moieties within the polymer in the formulation [ 146 ]. The difference in temperature inside and outside the body is typically large enough to induce the crosslinking of the gels as well as trigger drug release [ 140 ], but the rate limiting factor to drug release is thermal diffusion [ 144 ]. pH-responsive hydrogels are amongst the most studied stimuli-sensitive gels used in pharmaceutical research.…”

“…Hydrogels for intravitreal drug delivery are advantageous because they take up small volumes within the vitreous space and are biodegradable. They are also useful for circumventing the need for frequent repeat injections—which presents several risks and complications to patients—by acting as a drug depot even for unstable protein molecules [ 140 ]. There are a number of in-situ gelling systems reported for ocular delivery of proteins [ 225 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 ].…”

Material, Immunological, and Practical Perspectives on Eye Drop Formulation

“…Many hydrogels are responsive to ionic and pH changes 69p,82a,90. A strong interaction between the drug and the carrier may change the release profile of the delivery device, hindering delivery, and preventing the drug from reaching or sustaining the therapeutic threshold 91. The mechanism of drug loading is also important, as different methods create different release profiles but also involve different solvents 92.…”

“…[69p,82a,90] A strong interaction between the drug and the carrier may change the release profile of the delivery device, hindering delivery, and preventing the drug from reaching or sustaining the therapeutic threshold. [91] The mechanism of drug loading is also important, as different methods create different release profiles but also involve different solvents. [92] The loading of nanoparticles is also limited by the fact that the encapsulated phase makes up a very small fraction of the overall mixture, and the loading is limited to the equilibrium point between the phases.…”