Intravitreal Drug Delivery Research Articles

Zur Behandlungsstrategie bei chronischer endogener Uveitis

The treatment of chronic endogenous uveitis has included the use of local and systemic corticosteroids since the early 1950 s, and these still constitute the first-line option in the treatment, once an infectious aetiology has been excluded. Since the 1960 s, broad experience has been collected with antiproliferative and alkylating agents, and since the 1980 s several immunosuppressants have been employed in the therapy for endogenous uveitis. It has been recognised that the therapeutic response is not only related to a specific uveitic entity, but also to the genetic background of the individual. Therefore, no clear guide lines for therapy exist and, for most of the drugs, controlled studies are not available. Vitrectomy and intravitreal drug delivery have been added as local options on top or in case of failure of systemic therapies. The advent of biological agents, however, i. e. the introduction of interferon alpha and TNF alpha blocking agents, has opened a new era in the treatment of immunogenetic and autoimmune disorders. Evidence-based knowledge and personal experience have been reviewed to provide an update on the therapeutic strategy for chronic endogenous uveitis. The newly introduced biologicals seem to represent an interesting addition to the existing therapeutic options. Informations pertaining to efficacy and side effects of a long-term treatment of uveitis are, nevertheless, as yet not available.

Randomized Controlled Study of an Intravitreous Dexamethasone Drug Delivery System in Patients With Persistent Macular Edema

To evaluate a dexamethasone intravitreous drug delivery system (DDS) in patients with persistent (> or =90 days despite treatment) macular edema. This 6-month study randomized 315 patients with persistent macular edema with best-corrected visual acuity (BCVA) of 20/40 to 20/200 in the study eye to observation or a single treatment with dexamethasone DDS, 350 or 700 microg. Proportion of patients achieving a BCVA improvement of 10 or more letters or 15 or more letters, safety measures, change in fluorescein angiographic leakage, and central retinal thickness. At day 90 (primary end point), an improvement in BCVA of 10 letters or more was achieved by a greater proportion of patients treated with dexamethasone DDS, 700 microg (35%) or 350 microg (24%), than observed patients (13%; P<.001 vs 700-microg group; P = .04 vs 350-microg group); an improvement in BCVA of 15 letters or more was achieved in 18% of patients treated with dexamethasone DDS, 700 microg, vs 6% of observed patients (P = .006). Results were similar in patients with diabetic retinopathy, vein occlusion, or uveitis or Irvine-Gass syndrome. During 3 months of observation, 11% of treated patients and 2% of observed patients had intraocular pressure increases of 10 mm Hg or higher. In persistent macular edema, a single dexamethasone DDS treatment produced statistically significant BCVA improvements 90 days after treatment and was well tolerated for 180 days. Application to Clinical Practice Dexamethasone DDS, 700 microg, may have potential as a treatment for persistent macular edema.

Hydraulic flow and vascular clearance influences on intravitreal drug delivery.

A recent paper proposed a model for hydraulic flow inthe eye, claiming this could affect intravitreal drug administration. The impact of flow on various modes of administration was investigated in a physiologically accurate ocular model of the rabbit eye. Hydraulic flow initiated at the hyaloid was simulated in a three-dimensional finite element model including effects of convection and episcleral efflux. The interrelation between hydraulic and vascular clearance was treated using a method in which choroidal clearance is effected by simple boundary conditions, diminishing computing requirements. Drug diffusion coefficient and clearance rates for the choroid and anterior chamber were varied. Volumes and velocities of fluid flow permeating the vitreous agreed with literature values. Hydraulic flow impacted clearance of compounds not eliminated by the choroid; agreement with experimental data justified assuming perfect aqueous humor mixing. Hypertensive pressure produced up to a maximum 4-fold change in vitreal drug content from an intravitreal device depending upon location, orientation of the releasing surface, but was less important than vascular clearance strength and diffusion coefficient. The influence of intraocular pressure ([OP)-induced hydraulic flow is not likely to be of clinical significance for low molecular weight drugs that are efficiently cleared by the choroid.

In Vivo/In Vitro Correlation of Intravitreal Drug Delivery from Biodegradable Polymer Implants.

An approach for predicting the drug concentration in the vitreous body has been proposed for intravitreal drug delivery by biodegradable polymer implants. The release rates of a model drug, dexamethasone sodium m-sulfobenzoate (DMSB), from poly lactic acid implants were measured under in vitro and in vivo conditions using Japanese albino rabbits. The pharmacokinetic model assuming the cylindrical vitreous body was then solved together with the in vivo release rate and the other model parameters determined separately. The mathematical model successfully described the drug concentration–time profile in the vitreous body. The in vivo concentration–time profile in the rabbit vitreous body agreed with the one predicted on the basis of the in vivo release profile. The in vivo concentration–time profile in the vitrectomized eye was well predicted from the in vitro release profile. These findings may suggest that if the in vivo release profile is known or predicted, the in vivo concentration in the vitreous body can be evaluated by the help of computer simulation without carrying out the in vivo release experiment which is usually time-consuming for controlled release formulations.

Intravitreal acetylsalicylic acid in silicone oil: pharmacokinetics and evaluation of its safety by ERG and histology.

A new method of intravitreal drug delivery of acetylsalicyclic acid (AS) in silicone oil was investigated for safety and for its pharmacokinetics in the posterior pole of the eye. The AS was mixed in silicone oil to a concentration of 1.67 mg/ml. After vitrectomy, 15 NZW rabbits received an intravitreal injection of AS/silicone oil suspension. Clinical examination, pre- and postoperative electroretinography (ERG) and histology were performed. The pharmacokinetics of the distribution of salicylic acid was determined by HPLC analysis at 6 h, 24 h and 5 days in optic nerve, retina, choroid, vitreous, and blood. Clinical examination and histology revealed no adverse effects or signs of toxicity. The ERGs showed no significant difference between the pre- and postoperative results. The salicylic acid concentrations demonstrated peak values in the residual vitreous (640.0 micrograms/ml), choroid (446.0 ng/mg) and retina (281.3 ng/mg) at 6 h. At 24 h, the salicylic acid concentration decreased to 20.9 micrograms/ml in the residual vitreous and to 38.5 ng/mg in the retina. At 5 days the retinal level was still 48.1 ng/mg. AS delivery by intravitreal administration of loaded silicone oil is a safe method and results in high concentrations of salicylic acid in the posterior segment of the eye while maintaining low blood levels.

A pharmacokinetic model of intravitreal delivery of ganciclovir

A pharmacokinetic model of intravitreal drug delivery was developed for describing the elimination and distribution of ganciclovir in the eye following intravitreous polymeric delivery. The model was based on Fick's second law of diffusion and assumed a cylindrical vitreous body. The model parameters such as the diffusion coefficient and the partition coefficient of the drug in the vitreous body and its surrounding tissues were determined from in vitro experiments using rabbit tissues. The time course of in vivo mean concentration of ganciclovir in the rabbit vitreous body agreed well with the profile calculated from the present pharmacokinetic model for both membrane-controlled polymeric devices and biodegradable rod-matrix systems. The clinical vitreous concentration following implantation of the membrane-controlled delivery system was the same order of magnitude but approximately four times lower than that predicted from the present model. This may indicate the metabolism of ganciclovir and/or the facilitated transport across the retina/choroid membrane in the human eye.

Biodegradable scleral implant for intravitreal controlled release of fluconazole

PURPOSE. To evaluate the feasibility of using a biodegradable polymeric scleral implant containing fluconazole (FLCZ), a bis-triazole antifungal agent, as a potential intravitreal-controlled drug delivery system. METHODS. The scleral implants, loaded with 10, 20, 30, and 50% FLCZ, were prepared with biodegradable polymers of poly (DL-lactide-co-glycolide). Those with all loading doses were used for the in vitro release studies; those with 30% FLCZ were used for the intravitreal release studies in pigmented rabbits. The in vitro and in vivo release rates of FLCZ from the implants were measured periodically with spectrophotometry and high performance liquid chromatography, respectively. The effects of the implants on ocular tissues were evaluated ophthalmoscopically, histologically, and electrophysiologically. RESULTS. The scleral implants loaded with 10, 20, and 30% doses gradually released FLCZ over 4 weeks in vitro; those with 50% FLCZ released most of the drug in one week. FLCZ concentration in the rabbit vitreous remained within the 99% inhibitory concentration for Candida albicans for 3 weeks after implantation. The scleral implant gradually biodegraded, and it disappeared by 4 months after implantation. The electro-physiologic and histopathologic findings demonstrated no substantial toxic reactions in the ocular tissues. CONCLUSION. The current study suggests that a biodegradable, polymeric scleral implant containing FLCZ may be a promising intravitreal drug delivery system to treat fungal endophthalmitis.

In Vitro Evaluation of Polymeric Matrix and Porous Biodegradable Reservoir Devices for Slow-release Drug Delivery

Biodegradable polymeric devices were evaluated in vitro for intravitreal drug delivery. The matrix (short-term drug delivery) and the porous (longer-term drug delivery) reservoir devices were made from polycaprolactone of two molecular weights (30,000 and 56,000). Matrix devices were loaded with 5-fluorouracil or ganciclovir. Porous reservoirs were loaded with 5-fluorouracil, ganciclovir, 5-carboxyfluorescein, or foscarnet. The release was monitored in phosphate-buffered solution using ultraviolet spectrophotometry. Release from the matrix devices was characterized by an initial burst, followed by a nonlinear release. The porous reservoirs demonstrated zero order linear release of drugs, sustained up to 250 days in this experiment. The matrix device is capable of sustained release over several months; the porous reservoir can deliver drugs for over 1 year. Further studies are needed to evaluate in vivo biodegradation behavior and toxicity of drugs used for sustained release.

Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres.

We studied the biodegradation of and the tissue reaction to microspheres of 50:50 poly(D,L-lactic-co-glycolic)acid (PLGA) (viscosity-average MW: 3000 d), injected intravitreous in rabbits. These microspheres are under investigation as injectable devices for intravitreous sustained drug delivery. The rate of intravitreous degradation of PLGA microspheres has not been well documented in the literature. Twenty two pigmented rabbits underwent gas vitrectomy in one eye: 19 eyes received 2.5 mg of PLGA microspheres in 1 ml of balanced salt solution (BSS) and 3 control eyes received 1 ml of BSS only. Slit lamp exam and indirect ophthalmoscopy were performed periodically from day 1 to 6 months after surgery. The eyes were enucleated and studied by light microscopy and immunohistochemistry at various time points. The electroretinogram (ERG) was recorded in a subgroup of rabbits before injection and after 1 and 6 months. The amount of microspheres in the vitreous cavity progressively decreased. At 6 months microspheres were found in 1/4 rabbits at indirect ophthalmoscopy and in 4/4 rabbits histopathologically. A mild localized, non progressive foreign body reaction was observed. The cell reaction was composed mostly of vimentin and glial fibrillary acidic protein positive cells which probably represent glial cells and fibroblasts. The choroid and retina were normal. The ERG showed no abnormalities. No clinical inflammatory signs were observed 4 days postoperatively and thereafter.

In vivo/in vitro correlation of intravitreal delivery of drugs with the help of computer simulation.

The elimination of dexamethasone sodium m-sulfobenzoate, DMSB, following intravitreal injection, was measured in rabbit vitreous body under in vivo and in vitro conditions. The rate of elimination in vivo was appreciably greater than that in vitro, indicating that the in vivo data include not only the elimination due to metabolism/degradation in the vitreous humor, but also the elimination through the surrounding tissues such as the posterior aqueous humor, the retina/choroid/sclera membrane, and the lens. A general mathematical model based on Fick's second law of diffusion was developed for describing the pharmacokinetics of the intravitreal injection of DMSB. The model parameters were independently determined from a set of in vitro experiments. The in vivo data of elimination of DMSB following intravitreal injection agreed with the profiles calculated from the mathematical model, together with the model parameters determined from the in vitro experiments. The present in vivo/in vitro correlation, with the help of computer simulation, can be used for optimizing the therapeutic systems of intravitreal drug delivery.

An indwelling cannula system for the primate eye

An indwelling cannula system was designed as an instrument for chronic drug infusion into the vitreous cavity and tested in the cynomolgus monkey eye with repeated injections or continuous infusion using a pumping device. The cannula was passed through the pars plana and its tip situated in the vitreous cavity close to the macular area. Clinical observations up to 18 months did not reveal any adverse effects due to implantation. Histopathological observations from 1 week to 18 months after surgery revealed tissue proliferation around the cannula was minimal and localized only at the wound site, where proliferative tissue originated from the episclera and ciliary epithelium. Retina and choroid at the posterior pole showed normal morphology. Light microscopic autoradiograms demonstrated the function of this system. Injections of tritiated leucine through the cannula resulted in narrow bands of radioactive labelling of the photoreceptor outer segments corresponding to each injection. In contrast, chronic delivery using the pumping device resulted in a diffuse and wide band of labelling. These results strongly suggest that this system did not adversely affect the eye and that repeated intravitreal injections or chronic drug delivery into the vitreous are feasible using this system. Furthermore, autoradiographic results suggest that the drugs infused into the vitreous cavity spread readily into the retina.