Table 1.
Advanced DDS for IOP lowering.
| DDS Technology (Polymer) |
Drug | Advantages and Considerations | Administration Route | Stage | Reference | |
|---|---|---|---|---|---|---|
| Niosome-based polymers | ||||||
| Chitosan-coated Niosomes | Carteolol | -Increased retention time, gradual and sustained regulation of IOP -Relative Low-cost production -Biodegradable, chemically stable -Limited shelf life |
Topical | Preclinical- ex vivo and in vitro, in vivo | [56,57,58] | |
| Niosome gel | Pilocarpine Hydrochloride | |||||
| Latanoprost | ||||||
| Proniosome gel | Brimonidine tartrate | -Physically more stable than niosomes -Improved bioavailability and prolonged release |
Preclinical: in vitro and in vivo | [59,60] | ||
| Dorzalamide-HCl | ||||||
| Nanoparticles | ||||||
| PLGA Nanoparticles | Brinzolamide | -Sustained IOP reduction -Systemic absorption observed -Minimal toxicity |
Topical/ Subconjunctival | Preclinical- in vitro and in vivo | [46,47,106] | |
| γ-cyclodextrin nanoparticle | Candesartan and irbesartan | -Polymer improves bioavailability of drug -Angiotensin receptor blockers (ARB) potentially lower IOP-IOP varied individually in study |
Topical | Preclinical- in vivo | [49] | |
| PLGA nanoparticles | SA-2 (Nitric oxide) | -Additional neuro/cytoprotective effects through increasing antioxidant (SOD) activity-Slow, sustained release | Preclinical: in vitro and in vivo | [48] | ||
| Chitosan Nanoparticles | Nanobrimonidine | -Improved synthesis of <100 nm through novel method-Improved bioavailability through mucoadhesion | Preclinical: in vitro and in vivo | [50] | ||
| CMLLG and AMLLG-based Nanoparticles | Dorzolamide | -Used natural polymer (Galactomannans) for DDS, safer and economic-Prolonged IOP reduction | Preclinical: in vitro and in vivo | [51] | ||
| PDA/PEI Nanoparticles | miR-21-5p | -Improved transfection and stability of genetic material-Low cytotoxicity with PDA addition | Intracameral injection | Preclinical- in vitro and in vivo | [52] | |
| Mesoporous Silica Nanoparticles | ||||||
| Hollow mesoporous organosilica (HOS) nanocapsule | Nitric oxide | -Improved biodegradability of Mesoporous Silica Nanoparticles -Prolonged NO Donors increase IOP mediated by antioxidants -Improved cornea penetration -Enhanced bioavailability |
Topical | Preclinical- in vitro and in vivo | [53,54,107] | |
| Mesoporous silica nanoparticles | ||||||
| Polymer inserts | ||||||
| Chitosan and Chondroitin sulfate polymer insert | Benzamidine (4AD) | -Novel anti-glaucomatous agent -Additional neuroprotective effect -Extended-release capacity, lowers IOP |
Topical | Preclinical- in vitro and in vivo | [65,66,68] | |
| Chitosan/hydroxyethyl cellulose insert | Dorzolamide | -Modified biodegradable polymers to carry hydrophilic drugs-Dorzolamide had additional neuroprotective effect with sustained release | ||||
| Sodium alginate+ ethyl cellulose polymer inserts | Timolol maleate | |||||
| Chitosan ocular insert | Bimatoprost | -Similar effectiveness to Bimatoprost eyedrops up to 3 weeks -Small sample size |
Phase 2 Controlled study | [98] | ||
| Polymer films | ||||||
| Chitosan film | Brimonidine tartrate | -Eco-friendly drug synthesis overcoming poor solubility of chitosan -High cornea permeability |
Topical | Preclinical: in vitro and ex vivo | [67,69] | |
| β-cyclodextrin film with PBAE and GO layers | Brimonidine | -Time-controlled drug release for precise delivery -Preliminary study |
In vitro | |||
| Nanoemulsions | ||||||
| Nanoemulsion | Travoprost | -Enhanced absorption, prolonged IOP reduction-Long-term safety not investigated yet, toxicity with high surfactant levels and preservatives to be considered | Topical | Preclinical: in vitro and in vivo | [63,64] | |
| Brinzolamide | N/A | Ex vivo | ||||
| Implants | ||||||
| Silicone Implant contact lens (IM-R lens) | Timolol, Bimatoprost and hyaluronic acid | -Preservative-free -Prevents high initial burst release -Does not affect optical properties of lenses -Large drug loss during sterilization process |
Topical | Preclinical: in vitro and in vivo | [108,109] | |
| PCL thin-film implant | Timolol and Brimonidine | -Independently controlled co-delivery -Significant IOP reduction-Systemic absorption not measured |
Intracameral implant | Preclinical: in vitro and in vivo | [71,72] | |
| DE-117 Hypotensive agent | -Proprietary hypotensive agent used -Long-term effective IOP lowering and biocompatibility -Bulky device can cause corneal endothelium damage and device migration |
|||||
| Dexamethasone-PLGA copolymer implant | Bimatoprost | -Effective sustained release -Variability in biodegradation by 1-year mark in Phase 3 trial -Risk of corneal adverse reactions |
FDA-Approved-Durysta ™ | [99,100,101,110] | ||
| Gel-based polymers | ||||||
| Hybrid: PLGA-TPGS Nanoparticles in situ P407 gel | Brimonidine tartrate | -Stabilized nanodispersion using thermosensitive gel system | Topical | Preclinical- in vitro and in vivo | [74] | |
| Hybrid: CS-SA Nanogel | Timolol Maleate | -Novel nanocarrier method with increased stability -Sustained release, increased corneal permeation |
Preclinical: in vitro, ex vivo | [75] | ||
| Hybrid: Chitosan-based hydrogel | Curcumin nanoparticles and Latanoprost | -Thermosensitive -Sustained release -Preclinical cytotoxicity studies required |
Preclinical: in vitro and in vivo | [73,76,78,79,81] | ||
| P407/P188 gel | Timolol Maleate | |||||
| Chitosan-based hydrogel | Pilocarpine | Intracameral injection | ||||
| Hybrid: Nanovesicles in P407/Carbopol 934P gel | Bimatoprost | -Thermosensitive gel -Sustained release and effective in lowering IOP -No irritation, inflammation observed |
Topical and Subconjunctival injection | Preclinical: ex vivo, in vitro and in vivo | [77] | |
| Liposomes | ||||||
| Gelatinized core liposomes | Timolol Maleate | -Improved entrapment and stability -Prolonged IOP reduction |
Topical | Preclinical: in vivo and in vitro | [82,83,84] | |
| TPGS nanoliposomes | Brinzolamide | |||||
| Liposomes | Latanoprost and Thymoquinone | Subconjunctival injection | ||||
| Nanoliposome | Dorzolamide | -Extended duration of release -Complaints immediate of irritation and redness in both treatment groups |
Topical | Double-blind Randomized Controlled Trial | [105] | |
| Dendrimers | ||||||
| PAMAM Dendrimer | Timolol | -IOP-lowering effect -No signs of cytotoxicity and ocular irritation -Further pharmacokinetic profiling required |
Topical | Preclinical: in vitro and in vivo | [85,86] | |
| Brimonidine tartrate | ||||||
| Micelles | ||||||
| PEG-b-PPS Micelle | Peptide targeting FLT-4/VEGFR3 receptors | -Improved receptor targeting Nanocarriers -Sustained release and improvement in corneal permeability required |
Intracameral injection | Preclinical- in vitro and in vivo | [89] | |
| mPEG-PLA Micelles | Latanoprost and Timolol | -Sustained drug release, higher bioavailability -Did not affect optical properties -Lens can become rough after drug release |
Topical (Contact lens) | Preclinical: in vivo | [70] | |
| Other | ||||||
| PC- Self-Assembly Drug Nanostructures (SADN) | Dorzalamide-HCl | -Novel system-Enhanced corneal permeations-Sustained IOP lowering -No cytotoxicity data presented |
Topical | Preclinical: in vitro and in vivo | [87] | |
| Phase transition microemulsions (PMEs) | Brimonidine tartrate (BT) | -Novel system -Systemic absorption and related side effects may be prevented with method -Prolonged release |
Topical | Preclinical- in vitro and in vivo | [88] | |
| Microneedle | Hyaluronic Acid Hydrogel | -Extended IOP reduction without drugs or surgery -No significant complications -Repeated injections may cause fibrosis -Mechanistic studies further required |
Suprachoroidal injection | Preclinical: in vivo | [91] | |
| PG-HA Nanosuspensions | Acetazolamide | -Sustained drug release -Increased drug solubility -Dispersion characteristics maintained for 6 months |
Topical | Preclinical: in vitro and in vivo | [90] | |
| Ocular ring | Bimatoprost | -Effective sustained release -Reduction of IOP is lower compared to daily timolol solution |
Topical | Open-label extension to Phase 2 Clinical trial | [104] | |
| Cubosomes | ||||||
| GMO/P407 Cubosome | Acetazolamide | -Increased corneal permeation and ocular residence time-Good biocompatibility and no signs of cytotoxicity | Topical | Preclinical- ex vivo and in vivo | [61,62] | |
| Timolol Maleate | ||||||
| Montmorillonite-embedded polymers (Mt) | ||||||
| Mt-Eudragit Microsphere (MIDFDS) | Betaxolol hydrochloride (BH) | -Mt-Drug complex formed through ion exchange allows for longer controlled release of drug -DDS decreases cytotoxicity and hemolysis of drug |
Topical | Preclinical- in vitro and in vivo | [92,93,94,95,111] | |
| Mt-Solid Lipid Nanoparticles | Betaxolol hydrochloride (BH) | |||||
| Mt-PVA hybrid polymer | Brimonidine | |||||
| Mt/Chitosan Nanoparticles | Betaxolol Hydrochloride | |||||
| Electrospun polymers | ||||||
| PVA-Poloxamer 407 Nanofiber films | Timolol maleate | -Increased retention, drug loading, and sustained IOP lowering -All biocompatible sterilization for implants needs further investigation |
Topical | Preclinical- In vitro and in vivo | [96,97,112] | |
| Lutrol + PCL ocular implants | Acetazolamide | |||||
| SA-PVA nanofibers | Forskolin | |||||