Table 4.

Advanced DDS for anterior segment diseases.

Disease	Drug	DDS	Administration Route	Advantages and Considerations	Stage (Currently Used vs. Clinical Trial vs. Preclinical Trial)	Reference
Dry eye and corneal ulcer	Levofloxacin	HPMC and sodium alginate In situ gel	Topical	-pH-induced gel formation -Adjustable viscosity -High corneal permeability	Preclinical	[174]
Dry eye	cyclosporine A	mPEG-PLA micelles		-Extended shelf life -Reduced leakage of loaded drug -Larger drug retention in rabbit retina compared to the currently approved emulsion	Preclinical	[23]
Dry eye	Cyclosporine A	Cholesterol-hyaluronate nanomicelles	Contact lens	-Enhanced mechanical strength and wettability -Improved optical transmittance	Preclinical	[150]
Dry eye	Corticosteroid loteprednol etabonate	F127 nanomilled mucus penetrating nanoparticles	Topical	-Drug delivery surpasses the cellular inhibitory concentration of the carrier drug in vivo	Approved	[148]
Dry eye	Cyclosporine A	(HCO-40) and octoxynol 40 (OC-40). Polyvinylpyrrolidone, Sodium Phospate Monobasic Dihydrate, Sodium Phosphate Dibasic Anhydrous, and Sodium Hydroxide nanomicelles	Topical	-Higher bioavailability in vivo than free cyclosporine A -Minimal systemic leaking of Cyclosporine A	Clinical phase 3 completed	[189]
Dry eye	Rebamipide	2-hydroxypropyl-β-cyclodextrin and methylcellulose) and a gel base (Carbopol) nanoparticles	Topical applied to eyelids	-Prolonged release of Rebamipide -Sustained release exceeds the commercially available Rebamipide nanoparticles	Preclinical	[151]
Dry eye	Rebamipide	HSPC and Chol were dissolved in an appropriate amount of dichloromethane Multilamellar liposomes	Topical	-Prolonged retention time of RBM liposomes in the cornea -Clear solution increases patient compliance unlike the commercially available options	Preclinical	[152]
Dry eye	FK506	mono-functional POSS, PEG, and PPG hydrogel	Topical	-Long-acting ocular delivery system in murine animal model	Preclinical	[190]
Dry eye	flurbiprofen	N-acetylcysteine-chitosan oligosaccharide-palmitic acid nanomicelles	Topical	-Strong membrane association and prolonged precorneal retention	Preclinical	[187]
Sjogren’s dry eye	dexamethasone	PLGA and HPMC	Sub- conjunctival Implant	-Slow-release rate -High patient compliance	-Phase 3 clinical trials	[191]
Conjunctivitis	Rapamycin	poly (3- hydroxybutyrate-co-3-hydroxyvalerate) microsphere	Topical eye drops	-Trigger increased tear secretion -Reduced corneal fluorescein in vivo	Preclinical	[153]
Conjunctivitis	Ofloxacin	Chitosan and PVA nanofibers	Inserts	-Sustained release pattern for up to 96 h -Reduced burst release due to optimized crosslinking -9–20-fold higher bioavailability compared to the Ofloxacin solution	preclinical	[166]
Conjunctivitis	neomycin sulfate and betamethasone sodium phosphate	poloxamer 407 and chitosan hydrogel	Topical	-High encapsulation efficiency of hydrogels -Does not cause any irritation to the blood vessels	Preclinical	[167]
Conjunctivitis	Tacrolimus	Compritol, GMS, and dichloromethane solid lipid nanoparticles	Topical eye drop	-Rigid gel formation at 32 °C -In vivo evidence of superior pharmacodynamics compared to eye drops and solid lipid nanoparticles	Preclinical	[165]
Keratoconus	Riboflavin	Stearylamine or Trancutol P nanostructured lipid carriers	Topical	-Improves corneal crosslinking -High corneal transport	Preclinical	[168]
Keratoconus	riboflavin and dexamethasone	poloxamer 407 and HPMC gel	Topical	-Increases the cell thickness in relevant in vivo model	Preclinical	[169]
Keratoconus	Lactoferrin	Chitosan/TPP and Chitosan/Sulfobutylether-β-cyclodextrin Nanoparticles	Topical	-Host-guest complexation with BCD -Corneal residence time of more than 240 min	Preclinical	[170]
Corneal ulcer	phenytoin sodium	crown ether-based nanovesicles	Topical	-Spherical nanovesicles with very high entrapment efficiency -1.78-fold increase in corneal bioavailability compared to the drug suspension	Preclinical	[192]
Infectious Keratitis	hLF 1-11	HPMC and Hyaluronic Acid mucoadhesive matrices	unspecified	-6 months of antimicrobial activity -High stability of encapsulated peptides -Entrapment efficiency can be enhanced with Trehalose	Preclinical	[193]
Infectious Keratitis	moxifloxacin	HPMC with PVP and PEG	Ocular insert	-Adjustable concentration of HPMC and PVP reduces crystallization and increases the lamination consistency -Water encapsulation leads to increased bioadhesion -In situ gel formation prolongs the adhesion to the cornea	Preclinical	[176]
Bacterial Keratitis	Ofloxacin	chitosan and PEG-coated solid nanoparticles	Topical	-Slower drug release with 63.6% of the drug released in 3 h compared to 99.55% of the drug being released from the currently used DDS -Reduced average nanoparticle size -Accelerates ocular barrier permeation and increased adherence to the epithelium.	Preclinical	[194]
Fungal Keratitis	Amphotericin B	PVP and PVA patches	Microneedle ocular patch	-Does not contain deoxycholate that renders the currently available Amphotericin B ocular treatment painful -The microneedles completely dissolve within 1 minute in the cornea -More effective in targeting Candida compared to the liposomal amphotericin B-loaded microneedle ocular patch.	Preclinical	[195]
Fungal Keratitis	Amphotericin B	PVP and HA microneedles	Ocular patches	-Overcome the reduced loading capacity, reduced mechanical strength, and potentially high cost that could be associated with liposomal Amphotericin B formulations	Preclinical	[175]
Fungal Keratitis	Econazole	Carboxymethyl-alpha-cyclodextrin conjugated with chitosan	Topical eye drop	-Increased ocular bioavailability in the cornea by 29-times compared to controls in vivo and ex vivo after a single administration	Preclinical	[177]
Fungal Keratitis	Natamycin	Precirol ATO 5 and Pluronic f68 solid nanoparticles	Topical	-Extended drug release profile of 10 h -Increased corneal permeation compared to currently used formulation	preclinical	[196]
Keratitis and posterior uveitis	tacrolimus	PLGA, Tween, Cremophor, E80 solution, and PVA Nanocapsules	Topical eye drops	-Highly stable lyophilized DDS. -High retention and permeation of drug -Reduction in several inflammatory markers in the anterior chamber	Preclinical	[196]
Meibomian gland dysfunction	Cerium oxide nanoparticles	polyhydroxyethyl methacrylate contact lenses	Contact lenses	-In vitro and in vivo reduction of oxidative stress -Prolonged release	Preclinical	[162]
Meibomian gland dysfunction	Cyclosporin A	(Nano-cyclosporine; Cyporin N, Taejoon, Korea)	Topical	-Better corneal staining and increased lipid layer thickness compared to the group receiving the conventional cyclosporine formulation	Phase 3	[163]
Cataract disease	Cerium nanoparticles	PLGA-based nanoformulation	Topical	-Good biocompatibility -Avoids the need for subconjunctival injection	Preclincal	[185]
Cataract disease	Baicalin	mPEG-PLGA nanoparticles	Topical	-Improve precorneal residence time -Enhance the reduction of reactive oxygen species in vivo	Preclincal	[186]
Cataract disease	Lutein	Zein and PLGA	Topical	-Reduce cataracts in rat model -Fully biodegradable system emerging in the treatment of cataracts	Preclincal	[188]
Cataract disease	quercetin	Chitosan-N-acetylcysteine with hydroxypropyl β-CD	Topical	-Enhanced corneal permeability -Strong membrane association	Preclincal	[178]