Hollow nanoparticle and core-shell nanoparticle eye drops improve ocular retention and sustain release of drugs for up to 7 days. These strategies use either non-biodegradable materials, which can accumulate, or degradable materials with acidic degradation products that can trigger an inflammatory response.
Colloidal drug aggregates (CDAs) are self-assembled, amorphous, drug-rich nanoparticles.
CDAs can achieve high-loading (typically >70%) drug formulations by stabilizing them with small amounts of excipients, such as polymers, proteins, lipids,indocyanine dyes or other small-molecule aggregators. This contrasts with the typical <10% drug loading in nanoparticle formulations. Although CDAs have been studied for oral and intravenous administration, their use in local delivery had not been investigated until this study.
Incorporating timolol CDAs into a new hyaluronan (HA)-oxime hydrogel prior to ocular injection achieves adequate local delivery and mitigates the leakage and rapid drug release seen with nanoparticles.
Since topical application of timolol maleate reduces intraocular pressure (IOP) in healthy rodents, this model was used to test the IOP-lowering effects of the slow release timolol palmitate CDAs in rats over 56 days following a single subconjunctival injection versus those of free timolol.
Timolol palmitate CDAs have a critical aggregate concentration of 2.72µM and sustained in vitro release over 28 days. Timolol palmitate CDAs are dispersed throughout in situ gelling hyaluronan-oxime hydrogel and injected into the subconjunctival space of rat eyes. The IOP is significantly reduced for at least 49 days with a single subconjunctival injection of timolol-palmitate CDAs compared to 6 hours for conventional timolol maleate.
The systemic blood concentrations of timolol are significantly lower, even after 6 hours, for timolol palmitate CDA-loaded hydrogel versus free timolol maleate, thereby potentially reducing the risk of systemic side effects. This innovative approach redefines the role of CDAs and provides a framework for long-acting ocular therapeutics, shifting their perception from a drug screening challenge to a powerful tool for sustained local drug delivery.
REFERENCE:
Dang M, Slaughter KV, Cui H, Jiang C, Zhou L, Matthew DJ, Sivak JM, Shoichet MS. Colloid-Forming Prodrug-Hydrogel Composite Prolongs Lower Intraocular Pressure in Rodent Eyes after Subconjunctival Injection. Adv Mater. 2025 Feb;37(8):e2419306.
doi: 10.1002/adma.202419306.
