Hyaluronic Acid: Its Versatile Use in Ocular Drug Delivery with a Specific Focus on Hyaluronic Acid-Based Polyelectrolyte Complexes

Abstract

Extensive research is currently being conducted into novel ocular drug delivery systems (ODDS) that are capable of surpassing the limitations associated with conventional intraocular anterior and posterior segment treatments. Nanoformulations, including those synthesised from the natural, hydrophilic glycosaminoglycan, hyaluronic acid (HA), have gained significant traction due to their enhanced intraocular permeation, longer retention times, high physiological stability, inherent biocompatibility, and biodegradability. However, conventional nanoformulation preparation methods often require large volumes of organic solvent, chemical cross-linkers, and surfactants, which can pose significant toxicity risks. We present a comprehensive, critical review of the use of HA in the field of ophthalmology and ocular drug delivery, with a discussion of the physicochemical and biological properties of HA that render it a suitable excipient for drug delivery to both the anterior and posterior segments of the eye. The pivotal focus of this review is a discussion of the formation of HA-based nanoparticles via polyelectrolyte complexation, a mild method of preparation driven primarily by electrostatic interaction between opposing polyelectrolytes. To the best of our knowledge, despite the growing number of publications centred around the development of HA-based polyelectrolyte complexes (HA-PECs) for ocular drug delivery, no review articles have been published in this area. This review aims to bridge the identified gap in the literature by (1) reviewing recent advances in the area of HA-PECs for anterior and posterior ODD, (2) describing the mechanism and thermodynamics of polyelectrolyte complexation, and (3) critically evaluating the intrinsic and extrinsic formulation parameters that must be considered when designing HA-PECs for ocular application.

Preparation of a Sunitinib loaded microemulsion for ocular delivery and evaluation for the treatment of corneal neovascularization in vitro and in vivo

“…SH exhibits good mucoadhesive capabilities, readily forming hydrogen bonds with glycoproteins within the aqueous layer of tears and acting as a protective coating on corneal epithelial cells. Such binding forces significantly increase the precorneal residence time of SH-based formulations ( Casey-Power et al, 2022 ). The viscosity of carriers also plays an important role in enhancing the corneal penetration ( Awwad et al, 2017 ).…”

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems, Part II: Long-Term Stability and Clinical Ocular Biopermanence

“…Numerous studies have described how an increase in residence time decreases the rate of drug elimination favoring the bioavailability and efficacy of the formulation [45,46]. Residence time on the ocular surface is related to viscosity [47].…”

“…Residence time on the ocular surface is related to viscosity [47]. The association between efficacy and the percentage of HA present in artificial tear has been studied in preclinical and clinical studies, concluding that formulations with higher percentages of HA and higher viscosities improved the signs and symptoms of the dry eye disease because the ocular residence time was increased [45,48,49]. The optimum viscosity of an eye drop was established between 15 to 50 mPa•s [50].…”

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems: Stability and Ocular Biopermanence

“…From these data, it was possible to see that the viscosity remained practically constant at 2–8 °C, while on days 15 and 30, a drop was observed in those stored at −20 °C. This may be explained due to changes in polymer conformation during the freeze/thaw processes [ 64 ]. The present cysteamine compounded formulation maintained the pseudoplastic behavior of HA previously described in the literature [ 65 , 66 , 67 ] during all storage times and conditions, by decreasing its viscosity with increasing shear force, as seen in Figures S3–S5 .…”