Excipients Beyond Preservatives in Ophthalmic Eye Drops: A Narrative Review with Clinical Implications

To synthesize the role of non-preservative excipients in ophthalmic eye drops, focusing on their impact on drug delivery, tear-film function, ocular surface tolerability, and clinical performance.

A targeted literature search of PubMed/MEDLINE, Web of Science, and Scopus was conducted to identify preclinical and clinical studies evaluating ophthalmic excipients beyond preservatives. Studies were categorized according to excipient class, functional role, formulation strategy, and clinical relevance.

Non-preservative excipients are active determinants of ophthalmic formulation performance. Polymers, mucoadhesives, and in situ gelling systems enhance lubrication and precorneal residence time; lipid-based emulsions support tear-film lipid-layer restoration and lipophilic drug delivery; surfactants and cyclodextrins improve aqueous solubility; and buffers, tonicity agents, chelators, and osmoprotectants contribute to stability, comfort, and epithelial protection. The strongest clinical evidence comes from artificial tears and dry eye formulations, where multi-excipient approaches generally provide greater benefit than single-component products. Evidence for advanced delivery systems is strong in preclinical models but less consistently translated into clinical outcomes. Preservative-free formulations are therefore not necessarily excipient-neutral, particularly in chronic topical therapy.

Ophthalmic excipients should be regarded as integral components of topical therapy. Rational formulation design and clinical selection should consider the complete excipient matrix to optimize efficacy, tolerability, adherence, and long-term ocular surface safety.