Intraocular Drug Delivery Systems Research Articles

Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir

In an earlier study, a novel intraocular drug-delivery system was reported in which hexadecyloxypropyl-phospho-ganciclovir (HDP-P-GCV) was used as a prototype. The hypothesis was that many biologically effective compounds could be modified to crystalline lipid prodrugs and could be delivered directly into the vitreous in a long-lasting, slow-release form. This study was undertaken to characterize this new drug-delivery system further, by using small particles of HDP-P-GCV and hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV). HDP-P-GCV was microfluidized into 4.4-microm (median) particles, injected into rabbit vitreous. The vitreous drug level was then measured at different time points. Crystalline HDP-cCDV was synthesized, suspended in 5% dextrose, and injected into the rabbit's vitreous at 10, 55, 100, 550, or 1000 microg in 50 microL vehicle per eye, to determine the highest nontoxic dose. The dose, 100 microg, was injected into 24 rabbit eyes, to evaluate pharmacokinetics; into 14 rabbit eyes with established HSV retinitis, to evaluate its efficacy; and into 58 rabbit eyes before herpes simplex virus (HSV) infection to evaluate its intraocular antiviral duration. Microfluidized particles of HDP-P-GCV showed an increased drug release rate compared with the large-particle drug formulation, with area under concentration-time curve (AUC) of 219.8 +/- 114.1 (n=3) versus 108.3 +/- 47.2 (n=3) for unmodified HDP-P-GCV during the 12-week period after a 2.8-micromole intravitreal injection. There was a 103% increase of the drug released from the microfluidized formulation of HDP-P-GCV versus the unmodified formulation. Intravitreal injections of HDP-cCDV at doses of 100 microg/eye or lower were not toxic. After the 100 microg/eye injections, HPLC analysis showed a vitreous HDP-cCDV level of 0.05 microM at week 5, which declined to 0.002 microM at week 8. The concentration at week 8 (0.002 microM) remained above the IC50 for cytomegalovirus (0.0003 microM). The pretreatment study demonstrated an antiviral effect that lasted 100 days after a single intravitreal injection. This crystalline lipid prodrug intravitreal delivery system is an effective approach to achieving sustained, therapeutic drug levels in the eye. Small microfluidized particles of HDP-P-GCV provide more rapid dissolution and higher vitreous drug levels.

Intraocular dexamethasone delivery system for corneal transplantation in an animal model.

To assess the efficacy of a new intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in a high-risk corneal transplantation model. Lewis rats that received orthotopic corneal transplants (Balb/c mice donors) were divided into three groups (six rats in each); group 1 received no treatment and served as controls, group 2 was treated with 0.1% betamethasone eyedrops three times daily for 6 weeks, and group 3 received DEX DDS in the anterior chamber at the time of transplantation. All grafts in the untreated control group were rejected within 8 days. In the betamethasone eyedrop group, five eyes (83%) were rejected during the 8-week study period. None of the grafts in the DEX DDS group was rejected. The administration of DEX DDS significantly prolonged the survival rate of the corneal grafts (p < 0.001, log-rank test). DEX DDS is effective in suppressing graft rejection in high-risk corneal transplantation.

Two clinical trials of an intraocular steroid delivery system for cataract surgery.

The authors determined the safety and efficacy of an intraocular dexamethasone drug delivery system (Surodex) in the treatment of inflammation after cataract surgery. Surodex is a biodegradable polymer that releases dexamethasone for 7 to 10 days after placement in the anterior segment. Study 1 was a prospective, randomized, double-masked phase II clinical trial of 90 cataract surgical patients that compared treatment with Surodex with treatment with a placebo drug delivery system and with no anti-inflammatory drug treatment. Study 2 was a separate prospective, randomized, double-masked study of 60 cataract surgical patients that compared treatment with Surodex with topical dexamethasone therapy. In the first study, Surodex was superior to placebo in suppressing postsurgical inflammation throughout the 60-day postoperative period, as judged by masked evaluator slit-lamp grading of cell and flare. The differences were statistically significant from postoperative day 3 through postoperative week 3. Most Surodex patients did not require topical corticosteroid by 2 weeks after surgery (93%) or by 2 months after surgery (88%). In the second study, Kowa laser flare meter readings were lower in Surodex patients throughout the 90-day postoperative period. The results were statistically significant at 4, 8, and 15 days after surgery. There were no notable adverse complications of Surodex in either study. The authors concluded that Surodex was safe and effective in suppressing postcataract surgery inflammation and appears to be a promising alternative to topical corticosteroids.—Thomas J. Liesegang

Phase II results of an intraocular steroid delivery system for cataract surgery

Objective To evaluate the safety and efficacy of an intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in treating postoperative inflammation after cataract surgery. Study design Multicenter, randomized, double-masked, parallel group study comparing two dose levels of the DEX DDS to concurrent placebo and no treatment control subjects. Participants Ninety patients scheduled to undergo extracapsular cataract extraction with phacoemulsification and intraocular lens implantation participated in the study. Intervention One or two DEX DDSs, each containing 60 μg of dexamethasone, were placed in the posterior chamber after cataract surgery. Patients receiving the placebo received a DDS composed of the same matrix with no active drug. In vivo rabbit studies have determined that the DEX DDS releases dexamethasone into the anterior chamber (AC) for approximately 7 to 10 days. Main outcome measures The AC cells and the AC flare were assessed over a 60-day postoperative period using slit-lamp examination by masked observers. The number and percent of patients in each treatment group requiring additional postoperative topical anti-inflammatory medication were compared. Results Ninety patients were randomized into 4 treatment groups (30 to the 2 DEX DDS group, 30 to the 1 DEX DDS group, 15 to the placebo DDS group, and 15 to the no treatment group). The control patients required the addition of topical steroids as rescue medication more frequently and sooner than patients receiving DEX DDS (80% vs. 7% at week 2) ( P < 0.001). Patients receiving DEX DDS showed a significant reduction in postoperative inflammation as assessed by the combined AC cell and flare scores when compared to the control group from day 3 ( P = 0.002) through week 3. The DEX DDS was well tolerated. No clinically significant difference in any safety evaluations, including intraocular pressure, was seen between the DEX DDS-treated and control groups. Conclusion The DEX DDS was safe and effective in suppressing postoperative inflammation after uncomplicated cataract surgery. Additional topical anti-inflammatory drops were not needed for most patients.

OCULAR TOXICITY OF VITREAL PLURONIC POLYOL F-127

To evaluate pluronic polyol F-127 (PF-127) as a vitreous substitute and an intraocular drug delivery system, a total vitrectomy was performed on 18 New Zealand rabbits (18 eyes). The vitreous was replaced with either PF-127 (9 eyes) or balanced salt solution (9 eyes). There was little difference clinically between the eyes containing PF-127 and the control eyes. Both groups showed mild postoperative inflammation, with no differences in intraocular pressures. Histopathologic findings for the control group showed no significant retinal alteration, and serial ERG findings were within normal limits. In contrast, the eyes containing PF-127 showed marked destruction of the retina by 2 weeks after surgery. The ERG amplitudes decreased dramatically to a flat tracing by 24 hours after surgery. Although it is attractive as a potential vitreous substitute, PF-127 is not safe for human use, at least at the concentration used.