Uday B. Kompella

Excised rabbit, porcine, and bovine eyes were injected in the suprachoroidal space with a cassette of 27 drugs, including 10 beta-blockers, 8 NSAIDs, and 9 corticosteroids, spanning a lipophilicity range (LogD _7.4 : −4.18 to 4.70). Drug concentrations in retina and vitreous humor were quantified by LC-MS/MS on both injected and non-injected sides. Most drugs were detected in both tissues, with higher concentrations on the injected side (0.04–3.69 fraction dose or FD/g) compared to the non-injected side (0.00–0.74 FD/g), after excluding eight outliers (drug–prodrug pairs and unstable drugs). Total retinal concentrations (0.07–1.88 FD/g) exceeded vitreous concentrations (0.02–0.40 FD/g). Across species, delivery decreased with eye diameter (rabbit > porcine > bovine). For individual species, multiple linear regression explained 70–83% of variance in retinal concentrations and 45–62% in vitreous concentrations using drug physicochemical properties. A unified equation incorporating 1/d² (d is eye diameter in cm), lipophilicity (LogD _7.4 ), molar solubility (LogS), and total polar surface area (TPSA) predicted concentrations in all species for a given tissue, explaining 74% of retinal and 93% of vitreous variance. Retinal delivery scaled for all species: Log FD/g = -1.121 + 0.255*LogD _7.4 + 0.106*LogS + 0.004*TPSA + 0.395*1/d ² . Vitreous humor delivery scaled for all species: Log FD/g = -1.898–0.047*LogD _7.4 − 0.051*LogS + 0.001*TPSA + 0.833*1/d ² . While this study evaluated static barriers, in vivo delivery is expected to be lower due to dynamic clearance mechanisms.

Sustained release of drugs by devices such as dexamethasone implant placed in vitreous humor can reduce the frequency of intravitreal injections. The duration over which the device provides therapeutic drug exposure is a critical parameter and so models for predicting ocular pharmacokinetics after placing the device in vitreous humor are valuable. This study developed a model using parameters from literature to predict concentrations in aqueous humor, vitreous humor, retina and sclera-choroid after placing Ozurdex in vitreous humor and validated the model using data reported in literature for rabbits and Cynomolgus monkeys. The model is based on ordinary differential equations representing mass balances in vitreous humor, retina, aqueous humor and sclera-choroid. Additionally, a partial differential equation representing mass balance in the lens is included. The model can be simplified to yield explicit expressions for concentration in all tissues. The results are in reasonable agreement with concentrations reported in literature, particularly considering the in vivo data variability and lack of dependence on fitting parameters in the model. The simulation results suggest that the duration of therapeutic concentration in the retina is longer than the drug release duration from the implant because drug diffuses into the lens, creating a depot. The drug depot in the lens eventually releases the drug back into vitreous humor, which increases the total duration over which the concentrations are efficacious. The model can be applied to other sustained release devices placed in vitreous humor or elsewhere in the eye. Graphical abstract

The purpose of this study was to determine corneal permeability and uptake in rabbit, porcine, and bovine corneas for twenty-five drugs using an N-in-1 (cassette) approach and relate these parameters to drug physicochemical properties and tissue thickness through quantitative structure permeability relationships (QSPRs). A twenty-five-drug cassette containing β-blockers, NSAIDs, and corticosteroids in solution at a micro-dose was exposed to the epithelial side of rabbit, porcine, or bovine corneas mounted in a diffusion chamber, and the corneal drug permeability and tissue uptake were monitored using an LC-MS/MS method. Data obtained were used to construct and evaluate over 46,000 quantitative structure–permeability (QSPR) models using multiple linear regression, and the best-fit models were cross-validated by Y-randomization. Drug permeability was generally higher in rabbit cornea and comparable between bovine and porcine corneas. Permeability differences between species could be explained in part by differences in corneal thickness. Corneal uptake between species correlated with a slope close to 1, indicating generally similar drug uptake per unit weight of tissue. A high correlation was observed between bovine, porcine, and rabbit corneas for permeability and between bovine and porcine corneas for uptake (R² ≥ 0.94). MLR models indicated that drug characteristics such as lipophilicity (LogD), heteroatom ratio (HR), nitrogen ratio (NR), hydrogen bond acceptors (HBA), rotatable bonds (RB), index of refraction (IR), and tissue thickness (TT) are of great influence on drug permeability and uptake. When data for all species along with thickness as a parameter was used in MLR, the best fit equation for permeability was Log (% transport/cm²·s) = 0.441 LogD − 8.29 IR + 8.357 NR − 0.279 HBA − 3.833 TT + 10.432 (R² = 0.826), and the best-fit equation for uptake was Log (%/g) = 0.387 LogD + 4.442 HR + 0.105 RB − 0.303 HBA − 2.235 TT + 1.422 (R² = 0.750). Thus, it is feasible to explain corneal drug delivery in three species using a single equation.

Due to high structural flexibility, multidrug carrying capability, and tunable size, dendrimers have been used as suitable carriers for ophthalmic drug delivery. Drug molecules can be either encapsulated or chemically coupled to dendrimers. The nanoscopic size, spheroidal shape, and cationic surface of polyamidoamine (PAMAM) dendrimers promote their interaction with the cornea and result in prolonged precorneal retention. Dendrimers could be further cross‐linked to produce three‐dimensional hydrogel networks or dendrimer hydrogels (DH). The properties of the DH can be readily adjusted to maintain both fluidity and adhesiveness, making them suitable for developing topical ocular drug formulations. Micro‐/nano‐ sized DHs, that is, dendrimer micro‐/nano‐ gels, have unique properties such as ease of administration, large specific surface area for adhesion, and drug targeting functionalities, making them attractive for ophthalmic drug delivery. This perspective reports advances in PAMAM dendrimer based drug delivery systems including drug conjugates and micro‐ and nano‐ gels to enhance and sustain the delivery of multiple anti‐glaucoma drugs, Dendrimer and dendrimer gel‐derived drug delivery systems hold great potential as multifunctional topical drug delivery systems for the eye.

Journal of Ocular Pharmacology and Therapeutics

The purpose of this study was to develop a validated LC-MS/MS analytical method for the simultaneous analysis of a large cassette containing a wide range o