Ocular Pharmacokinetic Model Research Articles

Conditions for modifying intraocular lenses as drug carriers for methotrexate using poly (lactic-co-glycolic acid).

The intraocular lens (IOL) can be used as a slow-release drug carrier in cataract surgery to alleviate posterior capsular opacification (PCO). The following is a systematic development of an IOL using methotrexate and the solvent casting process with poly (lactic-co-glycolic acid) (PLGA) as a carrier polymer. Different solvents for PLGA and methotrexate were tested for dissolution properties and possible damage to the IOL. The required biological concentration of methotrexate was determined in human capsular bags implanted with an IOL. To detect fibrosis, α-SMA, f-actin, and fibronectin were labelled by immunofluorescence staining. Cell proliferation and extracellular matrix contraction were observed in a lens epithelial cell line (FHL-124). Finally, the IOL was designed, and an ocular pharmacokinetic model was used to measure drug release. Solvent mixtures were found to allow coating of the IOL with drug and PLGA without damaging it. PCO in the capsular bag model was inhibited above 1 μM methotrexate (p = 0.02). Proliferation in FHL-124 was significantly reduced above a concentration of 10 nM (p = 0.04) and matrix contraction at 100 nM (p = 0.02). The release profile showed a steady state within therapeutic range. After determination of the required physicochemical manufacturing conditions, a drug releasing IOL was designed. A favourable release profile in an ocular pharmacokinetics model could be shown.

Inhibition of proliferative vitreoretinopathy by a newly developed methotrexate loaded drug carrier in vitro

PurposeRepeated intravitreal injections of methotrexate for proliferative vitreoretinopathy, a rare ocular condition that can cause vision loss, have shown beneficial effects in recent clinical studies. The purpose of this study was to develop a slow-release, long-term drug carrier composed of the polymer polylactide-co-glycolide and methotrexate that can be injected intravitreally. MethodsThe required composition of the drug carrier was modeled using pharmacokinetic parameters based on current literature. Release kinetics were determined using an ocular pharmacokinetic model. Epiretinal PVR-membranes were harvested during pars plana vitrectomy and subsequently transferred to cell culture. The effect of the drug carrier on cell migration was investigated using time-lapse microscopy and a scratch-induced migration assay. The colorimetric WST-1-assay and a live-dead-assay were performed to determine viability, and the BrdU-assay was applied for proliferation. ResultsThe release profile showed an initial and a final burst of methotrexate with an intervening steady state that lasted 9–11 weeks. It showed inhibitory effects on pathobiological processes in human PVR-cells in vitro. Cell velocity in the time-lapse assay, migration in the scratch assay (p = 0.001), and proliferation in the BrdU assay (p = 0.027) were reduced after addition of the drug carrier. These effects occurred without causing a reduction in viability in the WST-1 assay (p > 0.99) and the live-dead assay. ConclusionThe methotrexate-loaded drug carrier can maintain a stable concentration for 9–11 weeks and influence the pathobiological process of PVR cells in vitro. Therefore, it represents a potential therapeutic orphan drug for PVR.

Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation Based on Concentration Dynamics in the Vitreous, Retina, and Aqueous Humor

PurposeTo estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (Dret) and the combined retinal pigment epithelium-choroid (DRPE-cho) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye.MethodsVitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate Dret and DRPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (Vinit), and neural retina/vitreous partition coefficients (Kret/vit) were tested. Sensitivity analysis was performed for the final model.ResultsWith the final IgG model (IOP 10.1 Torr, Vinit 400 μl, Kret/vit 0.5), the estimated Dret and DRPE-cho were 36.8 × 10−9 cm2s−1 and 4.11 × 10−9 cm2s−1, respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter “aqueous humor formation rate” sets constraints that need to be considered in the parameter estimation.ConclusionsThis study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.

Drug Penetration of the Posterior Eye Tissues after Topical Instillation: In Vivo and in Silico Simulation

The purpose of this study was to analyze drug pharmacokinetics in the posterior eye tissues after topical instillation. For the in vivo study, the concentrations of ofloxacin in rabbit ocular tissues were analyzed by high performance liquid chromatography at 1, 2, and 3 h after instillation. For the in silico simulation, the concentration distribution of ofloxacin in the eye was calculated by the ocular pharmacokinetic model based on the diffusion/partition model. The simulated profiles were then compared with the in vivo experimental findings. In the in vivo study, the drug concentration in the posterior vitreous body initially decreased with time after topical instillation, and thereafter, the concentration increased. The in silico simulation of ocular pharmacokinetics indicated that the drug penetration of the posterior vitreous body was determined by three major pathways: (1) the initial transscleral penetration, (2) the intermediate transcorneal penetration, and (3) the late transretinal penetration. The in vivo findings were well described by a series of contributions by these three pathways. In conclusion, the present in vivo and in silico studies suggest that the instilled drugs initially reached the posterior vitreous body by diffusion through the sclera and then later by corneal penetration and systemic circulation.

Ophthalmic delivery of cyclosporine A by punctal plugs

Dry eyes are treated by instillation of eye drops of cyclosporine A emulsion or by punctal plug insertion in canaliculus to block tear drainage. This paper focuses on a novel approach of developing a punctal plug that can also release cyclosporine A to provide a dual mechanism for treating dry eyes. The punctal plug consists of a cylindrical hydroxy ethyl methacrylate core containing drug microparticles surrounded by an impermeable silicone shell that covers about 50% of the core, with the uncovered part directed towards the eyes. The geometry of this design is significantly different from those in patent literature, which are mostly designed to be rods. Plugs release cyclosporine A for a period of about 3 months at zero-order at a rate of about 3 μg/day. The in vivo release rates are expected to be about half of this value. A mathematical model is presented that provides an accurate estimate of the release without any fitting parameter. Pharmacokinetic models are also developed for drug delivered through Restasis® and punctal plugs, and based on these models the release rate of about 1.5 μg/day may be therapeutically effective. The predictions of the ocular pharmacokinetic model are in reasonable agreement with reported measurements in humans.

Mucoadhesive Properties of Chitosan-Coated Ophthalmic Lipid Emulsion Containing Indomethacin in Tear Fluid

To evaluate the residence of chitosan-coated emulsion (CE) containing indomethacin in tears, the drug retention of CE in tear fluid was compared with non-coated emulsion (NE) after instillation in rabbit eyes. CE had mean concentrations 3.6-fold and 3.8-fold higher than NE at 0.5 h and 0.75 h after instillation, respectively. Mean residence time and half-life of CE were lengthened to 1.5-fold and 1.8-fold those of NE, respectively. Volume of distribution of CE in tear fluid was also 1.6-fold greater than that of NE. These findings indicated that retention of the drug in tears was appreciably prolonged by chitosan-coated emulsion, and that CE had higher distribution on the ocular surface than NE. The drug levels in cornea, conjunctiva, and aqueous humor at 1 h after instillation were clearly higher than those of NE. In a generalized ocular pharmacokinetic model, the ratio of CE to NE for peak concentration values (C(max)) and the area under the concentration/time curve (AUC) nearly corresponded to aqueous humor levels in vivo. Additionally, tensile testing showed that the force of detachment between CE and mucin was significantly larger than that of emulsion containing hydroxypropylmethyl cellulose (HPMCE) with a viscosity similar to CE; the forces of detachment of CE and HPMCE measured using phosphate-buffered saline (PBS) were almost the same since these formulations have similar viscosity. Mucoadhesive strength of CE was confirmed by measurements of force of detachment between formulations and mucin. The residence time of the emulsion in tear fluid was prolonged by chitosan coating because of its mucoadhesive properties.

Formulation Study of Eye Drop and Ocular Pharmacokinetic Model

Formulation Study of Eye Drop and Ocular Pharmacokinetic Model

A Pharmacokinetic Model for Ocular Drug Delivery

A pharmacokinetic model of ocular drug delivery has been developed for describing the elimination and distribution of ocular drugs in the eye. The model, based on Fick's second law of diffusion, assumes a modified cylindrical eye with three pathways for drug transport across the surface of the eye: the anterior aqueous chamber, the posterior aqueous chamber and the retina/choroids/scleral membrane covering the vitreous body. The model parameters such as the diffusion coefficient and the partition coefficient in various eye tissues can be evaluated from the in vitro membrane penetration experiments using a side-by-side diffusion cell system. The diffusion coefficient for a drug is also predicted by taking account of the effect of the molecular weight of model compounds. The present ocular pharmacokinetic model, which can predict the local concentration distribution in the eye, has well described the in vivo concentration profile in the various eye tissues, the lens, the aqueous humor and the vitreous body, following not only topical eye drop instillation but systemic administration as well. The present model also simulates the effects of binding and metabolism in the eye as well as the individual difference in ocular functions and structure such as cataract surgery and vitreous fluidity on the distribution and elimination of drug molecules in the eye.

Pharmacokinetic prediction of the ocular absorption of an instilled drug with ophthalmic viscous vehicle.

We previously developed an in vivo pharmacokinetic model that accounts for the corneal diffusion in albino rabbits and predicts the concentration of beta-blockers in the anterior segments. The purpose of this study is to pharmacokinetically predict the ocular absorption and characterize the systemic absorption of instilled drug with ophthalmic viscous vehicle to assist in its design and evaluation. Tilisolol and carboxymethylcellulose sodium salt (CMC) were used as the model ophthalmic drug and viscous polymer, respectively. After instillation of tilisolol with CMC vehicle in rabbits, the disposition of the drug in tear fluid, aqueous humor, and plasma were determined by HPLC. The ocular and systemic absorption were analyzed by a mathematical model including a diffusion process and a two-compartment model with first-order absorption, respectively. CMC vehicle increased the area under the concentration-time curve (AUC) of tilisolol in the tear fluid and aqueous humor and slightly reduced the AUC in plasma. The concentrations of tilisolol in the aqueous humor after instillation with CMC vehicle were accurately predicted from the tear concentrations by using the in vivo ocular pharmacokinetic model. CMC vehicle improved the ocular delivery of tilisolol.

Ocular pharmacokinetic models of clonidine-3H hydrochloride.

A single topical instillation of clonidine-3H HCl solution (0.2%) was administered to the rabbit eye (30 microliter) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180 min. By 45-60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constant ka, 0.00139 min-1, aqueous humor elimination rate constant k10, 0.0658 min-1; mean residence time MRTd, 35.6 min; apparent steady-state volume of distribution Vss, 0.530 ml; and ocular clearance Qe, 14.9 microliter/min. The fraction absorbed from the single instillation is estimated as 0.0163.