Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration
Abstract
:1. Introduction
2. Results
2.1. Topical Application of Rifampicin Reaches the Retina
2.2. Pharmacokinetic Studies Using a 0.25% Rifampicin Eye Drop Formulation
2.3. Preclinical Efficacy
2.4. Determination of Effective Dose of Rifampicin in Mouse Laser-Induced CNV Models
2.5. Ocular Tissue Delivery of Rifampicin via Oil-Based, Water-Based Suspension, and Water-Solubilized Formulations by Topical Applications
2.6. Oil-Based Formulation Plasma Exposure
2.7. Sub-Retinal and Retinal Delivery of Rifampicin via Oil-Based Formulations
Mouse effective AUC (h·ng/mg tissue) | Sub-retinal AUC by oil-based formulation C 0.01% rifampicin (h·ng/mg tissue) | Sub-retinal AUC by oil-based formulation C 0.001% rifampicin (h·ng/mg tissue) | |
AUC values | 0.27 | 0.01 | 0.001 |
Folds Greater Than Effective AUC | X1 | X0.04 | X0.004 |
Mouse effective AUC (h·ng/mg tissue) | Sub-retinal AUC by oil-based formulation E 0.1% rifampicin (h·ng/mg tissue) | Sub-retinal AUC by oil-based formulation E 0.01% rifampicin (h·ng/mg tissue) | |
AUC values | 0.27 | 0.27 | 0.18 |
Folds Greater Than Effective AUC | X1 | X1 | X0.7 |
3. Discussion
4. Materials and Methods
4.1. 0.25% and 0.5% Rifampicin Water-Based Solubilized Formulations
4.2. Topical Application of Rifampicin Reaches the Retina in Rat
4.3. Pharmacokinetic Studies Using a 0.25% Rifampicin Eye Drop Formulation
4.4. Preclinical Efficacy
4.5. Determination of Effective Dose of Rifampicin in Mouse Laser-Induced CNV Models
4.6. Oil- or Water-Based Formulations
4.7. Ocular Tissue Delivery of Rifampicin via Oil-Based, Water-Based Suspension, and Water-Solubilized Formulations by Topical Applications
4.8. Oil-Based Formulation Plasma Exposure
5. Conclusions
6. Patents and Patent Applications
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound (Brand Name) Mechanism of Action for Indication or Usage | Drug Amount Administered | Drug Amount Detected in Retina |
---|---|---|
Betoptic 0.5% (MW: 307) Beta 1 receptor blocker for glaucoma [39] | 0.5% 4 drops (120–200 μL, 600–1000 μg) | 300 ng/ 1 g of retinal tissues (Rabbit, average of n = 5) |
0.5% 8 drops (240–400 μL, 1200–2000 μg) | 480 ng/ 1 g of retinal tissues (Rabbit, average of n = 7) | |
Dexamethasone (MW: 392) Glucocorticoid for inflammation [40] | 0.5% 50 μL, 250 μg | 33 ng/ 1 g of retinal tissues (Rabbit, average of n = 6) |
Rifampicin | 0.25% 3 drops (15 μL, 37.5 μg) | 1280 ng/ 1 g of retinal tissues (Rat) SE: 394.0348 |
0.25% 10 drops (50 μL, 125 μg) | 2939 ng/ 1 g of retinal tissues (Rat) SE: 50.54041 |
(n = 3, Average) Mouse effective AUC (h·ng/mg tissue) | AUC by oil- based formulation A (h·ng/mg tissue) | AUC by oil- based formulation B (h·ng/mg tissue) | AUC by oil- based formulation C (h·ng/mg tissue) | AUC by oil- based formulation D (h·ng/mg tissue) | |
AUC values | 0.27 | 0.96 | 1.37–2.11 | 2.18–2.68 | 4.40 |
Folds Greater Than Effective AUC | X1 | X4 | X5–X8 | X8–X10 | X16 |
AUC by oil- based formulation E (h·ng/mg tissue) | AUC by oil-based suspension formulation F (h·ng/mg tissue) | AUC by water-based suspension formulation G (h·ng/mg tissue) | AUC by water-based solubilized formulation H (h·ng/mg tissue) | AUC by water-based solubilized formulation RK32 (h·ng/mg tissue) | |
AUC values | 8.77 | 0.62 | 1.82 | 1.33 | 2.05 |
Folds Greater Than Effective AUC | X32 | X2 | X7 | X5 | X8 |
(n = 3, Average) Mouse effective AUC (h·ng/mg tissue) | AUC by oil- based formulation A (h·ng/mg tissue) | AUC by oil- based formulation B (h·ng/mg tissue) | AUC by oil- based formulation C (h·ng/mg tissue) | AUC by oil- based formulation D (h·ng/mg tissue) | |
AUC values | 0.27 | 0.27 | 0.31–0.46 | 0.74 | 1.31 |
Folds Greater Than Effective AUC | X1 | X1 | X1–X2 | X3 | X5 |
AUC by oil- based formulation E (h·ng/mg tissue) | AUC by oil- based formulation F (h·ng/mg tissue) | AUC by water-based suspension formulation G (h·ng/mg tissue) | AUC by water-based suspension formulation H (h·ng/mg tissue) | AUC by water-based solubilized formulation RK32 (h·ng/mg tissue) | |
AUC values | 1.06 | 0.17 | 0.52 | 0.46 | 0.22 |
Folds Greater Than Effective AUC | X4 | X1 | X2 | X2 | X1 |
A | B | C | D | RK32 | |
---|---|---|---|---|---|
Rifampicin (ng/mL plasma) | 0.70 | 0.47 | 1.59 | 1.96 | 10.24 |
SE | 0.2144 | 0.0982 | 0.2764 | 0.3129 | 0.9431 |
A | B | C | D | E | F | |
---|---|---|---|---|---|---|
Rifampicin | 1% | 1% | 1% | 1% | 1% | 1% |
White Petroleum | 99% | 79.2% | 49.5% | |||
Liquid Paraffin | 19.8% | 49.5% | 99% | |||
Sesame Oil | 99% | |||||
Light Liquid Paraffin | 99% | |||||
Viscosity (mPaS) | 3815 | 2145 | 867 | 161 | 63 | 6 |
Shear Velocity (s−1) | 200 | 200 | 200 | 200 | 200 | 200 |
G | H | RK32 | |
---|---|---|---|
Rifampicin | 1% | 1% | 1% |
NaCl | 0.67% | 0.4% | |
Polyoxyethylene castor oil | 5% | ||
Ethylene glycol monostearate | 3% | ||
Cellulose polymers | 0.8% | 0.5% | |
Na2HPO4 | 0.3% | 1.5% | 1.5% |
EDTA | 0.1% | 0.1% | |
Anti-oxidants | 0.3% | 0.3% | |
pH | 7.1 | 7.0 | 8.3 |
Viscosity (mPaS) | 101 | 1.3 | 39.7 |
Shear Velocity (s−1) | 200 | 200 | 200 |
C (0.01% Rifampicin) | C (0.001% Rifampicin) | E (0.1% Rifampicin) | E (0.01% Rifampicin) | |
---|---|---|---|---|
Viscosity (mPaS) | 801 | 781 | 62 | 65 |
Shear Velocity (s−1) | 200 | 200 | 200 | 200 |
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Vailoces, V.A.S.; Tolentino, A.J.; Arevalo, J.F.; Adelman, R.A.; Bhisitkul, R.; Do, D.V.; Nguyen, Q.D.; Tolentino, M.J.; Tanito, M.; Serizawa, H. Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration. Pharmaceuticals 2025, 18, 655. https://doi.org/10.3390/ph18050655
Vailoces VAS, Tolentino AJ, Arevalo JF, Adelman RA, Bhisitkul R, Do DV, Nguyen QD, Tolentino MJ, Tanito M, Serizawa H. Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration. Pharmaceuticals. 2025; 18(5):655. https://doi.org/10.3390/ph18050655
Chicago/Turabian StyleVailoces, Valory Anne S., Andrew J. Tolentino, Jose Fernando Arevalo, Ron A. Adelman, Robert Bhisitkul, Diana V. Do, Quan Dong Nguyen, Michael J. Tolentino, Masaki Tanito, and Hiroaki Serizawa. 2025. "Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration" Pharmaceuticals 18, no. 5: 655. https://doi.org/10.3390/ph18050655
APA StyleVailoces, V. A. S., Tolentino, A. J., Arevalo, J. F., Adelman, R. A., Bhisitkul, R., Do, D. V., Nguyen, Q. D., Tolentino, M. J., Tanito, M., & Serizawa, H. (2025). Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration. Pharmaceuticals, 18(5), 655. https://doi.org/10.3390/ph18050655