Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives
Abstract
:1. Introduction
2. Intraocular Pharmacokinetics of Current Intravitreal Drugs
Drug | Species | Molecular Weight (kDa) | Intravitreal t1/2 (day) | Reference |
---|---|---|---|---|
Pegaptanib | Rhesus monkey | 40 | 3.92 | Drolet et al. [44] |
Ranibizumab | New Zealand rabbit | 48 | 2.51 (vitrectomized) | Ahn et al. [30] |
2.75 (nonvitrectomized) | ||||
2.18 | Park et al. [34] | |||
3.0 | Gaudreault et al. [10] | |||
3.2 | Shatz et al. [45] | |||
Dutch belted rabbit | 2.88 2.81 | Bakri et al. [8] Christoforidis et al. [46] | ||
Cynomolgus monkey | 1.4 (vitrectomized) | Niwa et al. [31] | ||
2.3 (nonvitrectomized) | ||||
2.54 | Gaudreault et al. [47] | |||
2.63 | ||||
Owl monkey | 2.73 | Christoforidis et al. [48] | ||
Human | 7.19 (nonvitrectomized) | Krohne et al. [27] | ||
Bevacizumab | New Zealand rabbit | 149 | 7.56 | Ahn et al. [33] |
6.51 | Sinapis et al. [49] | |||
Dutch belted rabbit | 4.32 | Bakri et al. [9] | ||
6.0 | Nomoto et al. [50] | |||
4.22 | Christoforidis et al. [46] | |||
Owl monkey | 3.60 | Christoforidis et al. [48] | ||
Human | 9.82 (nonvitrectomized) | Krohne et al. [26] | ||
11.67 | Meyer et al. [51] | |||
Aflibercept | New Zealand rabbit | 145 | 3.92 | Park et al. [34] |
Cynomolgus monkey | 1.5 (vitrectomized) 2.2 (nonvitrectomized) | Niwa et al. [31] | ||
Owl monkey | 2.44 | Christoforidis et al. [48] | ||
Abicipar pegol | Human | 34 | ≥13 days | Campochiaro et al. [52] |
Brolucizumab | New Zealand rabbit | 26 | 2.94 | FDA review [36] |
Cynomolgus monkey | 2.08 | |||
Human | 5 ± 2 | |||
Faricimab | Cynomolgus monkey | 150 | 2.83 (aqueous) | Regula et al. [37] |
Conbercept | Chinchilla rabbit | 143 | 4.24 | Li et al. [38] |
3. Efforts to Enhance the Intraocular Pharmacokinetics and Pharmacodynamics of Intravitreal Drugs
3.1. Dose Escalation of Intravitreal Drugs
3.2. Increasing the Molecular Weight of Intravitreal Drug Molecules
3.3. Sustained-Release Intravitreal Implants
3.4. Micro- and Nanoparticles
3.4.1. Microparticles
3.4.2. Dendrimer
3.4.3. Liposome
3.4.4. Polymeric Micelles
3.4.5. Polymeric Nanoparticles
3.4.6. Solid Lipid Nanoparticles
3.4.7. Coated Nanoparticles
3.4.8. Inorganic Nanoparticles
3.5. Hydrogels
3.6. Combined Drug Delivery Systems
3.7. Port Delivery Systems
4. Drug Administration Routes besides the Intravitreal Route
4.1. Topical Routes
4.2. Subconjunctival and Subtenon Routes
4.3. Suprachoroidal Routes
4.4. Subretinal Routes
4.5. Trans-Scleral Routes
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Route | Delivery Platform | Characteristics | Drug/Cargo | Development | Reference | |
---|---|---|---|---|---|---|
Intravitreal | Implants |
| Dexamethasone(Ozurdex) Fluocinolone acetonide (Retiset, Illuvien) Ganciclovir (Vitrasert) Brimonidine (Brimo DDS) | Launched Phase 2 | [62,63,64,65] | |
Micro-, Nano-particles | Microparticles |
| Triamcinolone (Kenalog, MaQaid, Trivaris, Triesence) Sunitinib Malate (GB-102) | Launched Phase 2 | [70,71,72,73,74,75,76,77,78] | |
Dendrimer |
| Anti-VEGF (Bevacizumab) Fluocinolone Acetonide Dexamethasone Triamcinolone Acetonide Neurotrophin 4 | Pre-clinical | [79,80,81,82,83,84,85] | ||
Liposome |
| siRNA DNA Anti-VEGF (Bevacizumab) | Pre-clinical | [86,87,88,89,90] | ||
Micelles |
| Dexamethasone Triamcinolone Acetonide Sirolimus Genistein | Pre-clinical | [91,92,93,94,95,96,97] | ||
Polymeric |
| Anti-VEGF (Bevacizumab) Fenofibrate | Pre-clinical | [98,99,100,101] | ||
Others |
| Anti-VEGF (Bevacizumab) Brimonidine | Pre-clinical | [102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118] | ||
Hydrogel |
| Anti-VEGF (Ranibizumab, Bevacizumab) Tyrosine kinase inhibitor | Phase 1 (Ocular therapeutix) | [119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135] | ||
Combined systems |
| Anti-VEGF (Ranibizumab, Bevacizumab) | Pre-clinical | [136,137,138,139] | ||
Port delivery system |
| Anti-VEGF (Ranibizumab) | Phase 3 | [140] | ||
Topical |
| Dexamethasone Regorafenib PAN-90806 | Phase 2 | [141,142,143,144] | ||
Subconjunctival | Hydrogel |
| Insulin Ovalbumin | Pre-clinical | [145,146,147,148,149,150,151,152,153,154,155,156,157] | |
Polymeric Nanoparticles | Budesonide Carboplatin Celecoxib | Pre-clinical | ||||
Suprachoroidal | Microneedle Microcannulation |
| Triamcinolone Acetonide | Phase 3 | [158,159,160,161,162,163,164,165,166,167,168,169,170,171,172] | |
Subretinal | Liposome Dendrimer Viral vector |
| siRNA Plasmid DNA Anti-VEGF genome | Pre-clinical Phase 1/2 | [173,174,175,176,177,178,179] | |
Trans-scleral | Iontophoresis |
| Dexamethasone Anti-VEGF (Bevacizumab) | Pre-clinical | [180,181,182,183,184,185,186,187] |
Drug Delivery Systems | Trial Name | Drug (Sponsor) | Description | Results |
---|---|---|---|---|
Dose escalation | HARBOR (NCT00891735) | Ranibizumab (Novartis) | Phase 3, interventional, multicenter, randomized, dose-comparison | 2.0 mg (4-fold dose escalation) showed similar treatment effect compared to 0.5 mg dose, whereas fewer required injections. |
SAVE (NCT01025232) | Ranibizumab (Novartis) | Phase 1/2a, interventional, open-label, multicenter | 2.0 mg (4-fold dose escalation) showed visual and anatomic gains in recalcitrant neovascular AMD. | |
READ 3 (NCT01077401) | Ranibizumab (Novartis) | Phase 3, interventional, multicenter, randomized, controlled, double-masked | 2.0 mg (4-fold dose escalation) showed no superior 24 months visual improvements compared to 0.5 mg dose in diabetic macular edema. | |
PHOTON (NCT04429503) | Aflibercept (Bayer) | Phase 3, interventional, multicenter, randomized, controlled, double-masked | Ongoing 8.0 mg (4-fold dose escalation) every 12 or 16 weeks after a loading phase in participants with diabetic retinopathy. | |
PULSAR (NCT04423718) | Aflibercept (Bayer) | Ongoing 8.0 mg (4-fold dose escalation) every 12 or 16 weeks after a loading phase in participants with neovascular AMD. | ||
HAWK (NCT02307682) | Brolucizumab (Novartis) | Phase 3, interventional, multicenter, randomized, active-controlled, double-masked | Brolucizumab 3 mg showed similar visual outcomes compared to aflibercept and resulted in fewer injections. | |
HARRIER (NCT02434328) | Brolucizumab (Novartis) | Brolucizumab 3 mg and 6 mg showed similar visual outcomes compared to aflibercept and resulted in fewer injections. | ||
Large molecule biopolymer | DAZZLE (NCT04049266) | KSI-301 (KODIAK) | Phase 2b/3, interventional, multicenter, randomized, controlled, double-masked | Ongoing//KSI-301 5 mg vs. Aflibercept 2 mg Prior phase 1 study (NCT03790852) resulted in visual improvements with 6-month interval intravitreal injections in neovascular AMD, diabetic macular edema and retinal vein occlusion subjects. |
Intravitreal implant | (NCT00658619) | Brimonidine (Allergan) | Phase 2, interventional, randomized, multicenter | Mean area of geographic atrophy secondary to neovascular AMD was reduced at month 12 in brimonidine implant compared to sham. |
Microparticles | ADAGIO (NCT03249740) | Sunitinib Malate (GB-102, GrayBug vision) | Phase 1/2a, interventional, randomized, multicenter | 88% patients at 3 months and 68% patients at 6 months were maintained on a single intravitreal injection. |
ALTISSIMO (NCT03953079) | Phase 2b, interventional, randomized, multicenter | Ongoing Compare the visual outcome after intravitreal administration of 1 mg and 2 mg GB-102, and aflibercept 2 mg dose in neovascular AMD. | ||
(NCT04085341) | Phase 2a, interventional, randomized, multicenter | Ongoing Diabetic macular edema and retinal vein occlusion. | ||
Hydrogel | CLN-0046 (NCT03630315) | OTX-TKI (Ocular Therapeutix) | Phase 1, interventional, open-label, randomized, controlled, multicenter | Ongoing Low dose vs. middle dose vs. high dose vs. OTX-TKI + Anti-VEGF. |
Port delivery system | LADDER (NCT02510794) | Ranibizumab (Novartis) | Phase 2, interventional, randomized, controlled, multicenter | Visual outcomes were similar in the ranibizumab-loaded port 100 mg/mL and monthly intravitreal injections at 9 months with the median time to initial refill was 15 months in the 100 mg/mL group. |
ARCHWAY (NCT03677934) | Ranibizumab (Novartis) | Phase 3, interventional, randomized, visual assessor-masked, active-comparator study | Ongoing Port delivery system 100 mg/mL vs. monthly intravitreal injection 0.5 mg (10 mg/mL) in neovascular AMD. | |
PAVILION (NCT04503551) | Ranibizumab (Novartis) | Ongoing Diabetic retinopathy. | ||
PAGODA (NCT04108156) | Ranibizumab (Novartis) | Ongoing Diabetic macular edema. | ||
Topical | DREAM (NCT02222207) | Regorafenib (Bayer) | Phase 2a/2b, interventional, randomized, multicenter | Among 51 subjects, 21 patients (41%) required intravitreal ranibizumab rescue due to the ocular treatment-emergent adverse events by week 12. |
(NCT03479372) | PAN-90806 (PanOptica) | Phase 1/2a, interventional, randomized, uncontrolled, double-masked, multicenter | Two, 6, or 10 mg/mL eye drops daily for 12 weeks No rescue therapy for 51% of patients. Eighty-eight percent of nonrescued patients showed clinical improvement or stability. | |
Suprachoroidal | TANZANITE (NCT02303184) | Triamcinolone Acetonide (Clearside Biomedical) | Phase 2, interventional, randomized, controlled, masked | Improved visual outcomes than aflibercept monotherapy. Lesser number of intravitreal injections. |
TYBEE (NCT03126786) | Phase 2, interventional, randomized, controlled, double-masked | No definite advantages of visual outcomes in diabetic macular edema with suprachoroidal CLS-TA + intravitreal aflibercept combined. | ||
PEACHTREE (NCT02595398) | Phase 3, interventional, randomized, controlled, double-masked | Better visual outcome and less ocular complication in noninfectious uveitis complicated by macular edema. | ||
Subretinal | (NCT03066258) | RGX-314 (Regenxbio) | Phase 1/2a, interventional, open-label, non-randomized, multiple-cohort, dose-escalation | Ongoing After initial ranibizumab injection, genomes were injected and anti-VEGF was treated after 4 weeks and as needed. At 6 months, visual outcomes were improved with less required intravitreal injections. |
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Kim, H.M.; Woo, S.J. Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives. Pharmaceutics 2021, 13, 108. https://doi.org/10.3390/pharmaceutics13010108
Kim HM, Woo SJ. Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives. Pharmaceutics. 2021; 13(1):108. https://doi.org/10.3390/pharmaceutics13010108
Chicago/Turabian StyleKim, Hyeong Min, and Se Joon Woo. 2021. "Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives" Pharmaceutics 13, no. 1: 108. https://doi.org/10.3390/pharmaceutics13010108
APA StyleKim, H. M., & Woo, S. J. (2021). Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives. Pharmaceutics, 13(1), 108. https://doi.org/10.3390/pharmaceutics13010108