An Intraocular Steroid Delivery System for Cataract Surgery
David F Chang
Accepted for publication 9 March 2001
(Surgical insertion of sustained release intraocular steroid pellet.)
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The use of peri-operative anti-inflammatory or antibiotic medication for cataract surgery continues to be the standard of care. Options for drug administration at the time of surgery include topical drops, subconjunctival injection, collagen shield, and intracameral injection or infusion. However, all of these methods fail to provide a prolonged therapeutic drug level. Because of the brief duration of drug levels achieved by intraoperative delivery methods, topical anti-inflammatory medication is prescribed postoperatively until the blood-aqueous barrier is re-established. Poor corneal penetration may limit the drug level attainable via the topical route.
In addition, topical therapy is associated with the well-recognized problems of patient compliance, patient inconvenience, and physician or staff time instructing patients. Compliance problems may result in improper dosing, frequency, or cul-de-sac instillation, improper preparation (e.g. contaminating a bottle or failure to shake it), and substitution of the wrong medication.
Oculex Pharmaceuticals, in Silicon Valley, has developed a unique sustained-release intraocular drug delivery system. The tiny, one mm long device consists of a biodegradable polymer which is inserted into the anterior or posterior chamber at the conclusion of surgery. The polymer is hydrolyzed into the natural byproducts of lactic and glycolic acid; and as it dissolves, any drug that has been bound to the polymer is gradually released at a programmed rate. Depending on the formulation, the drug can be released over the course of a week, or over as long a period as one year.
Their first product, Surodex, contains 60 ug of dexamethasone, approximately the same amount of drug contained in a single drop of topical Decadron (Merck). Rabbit studies have shown that the Surodex dexamethasone drug delivery system achieves a continuous aqueous steroid level for 7 - 10 days, after which if falls to low or nondetectable levels. In addition, the delivery system is able to achieve a much higher aqueous concentration in rabbit eyes, than is possible with topical dexamethasone.
To date, two human clinical trials investigating the safety and efficacy of Surodex have been completed. Following a small FDA Phase I study demonstrating no adverse problems, the US FDA Phase II study enrolled 90 cataract surgery patients at 4 different sites in a randomized, double masked placebo-controlled trial comparing Surodex to no treatment1. The comparison to no treatment was made because, at the time of the study, rimexalone was the only steroid that was FDA-approved for the treatment of postop inflammation, on the basis of a randomized controlled study versus placebo.
Following uncomplicated cataract surgery, the 90 patients were randomized in a 2:1 ratio into a treatment group that received Surodex, and a control group that received either no treatment or a placebo delivery particle. Masked slit lamp grading of cell and flare was carried out for two months postoperatively. No other anti-inflammatory medications - either topical or systemic - were permitted until postoperative day 3, at which time, the masked postoperative examiner could initiate topical steroid for postop iritis that was failing to improve. This was termed �rescue� medication.
The majority of Surodex-treated patients (88%) did not require �rescue� topical medication during the 2-month postop period, while the majority of the control group (83%) did. These differences were statistically significant (p <_0.001 at="at" every="every" post-operative="post-operative" visit="visit" from="from" day="day" _3="_3" on.="on." after="after" _2="_2" weeks="weeks" postop="postop" _-="_-" when="when" an="an" insignificant="insignificant" intraocular="intraocular" level="level" of="of" the="the" steroid="steroid" would="would" have="have" been="been" expected="expected" only="only" surodex="surodex" treated="treated" patients="patients" _5="_5" started="started" rescue="rescue" medication.="medication." this="this" suggests="suggests" that="that" rebound="rebound" inflammation="inflammation" was="was" not="not" a="a" frequent="frequent" occurrence="occurrence" with="with" treatment.="treatment." p="p">
Mean AC cells plus flare scores, as determined by masked slit lamp examination, were lower in the Surodex treated groups than in the control groups throughout the 60-day postop period. The differences were statistically significant at Day 3 and at Weeks 1, 2, and even by Week 3 (p=0.004), even though more than 80% of the control patients had received topical anti-inflammatory medications by this time. The continued low mean AC cell and flare scores after postop Week 2 further suggests that rebound inflammation was infrequent despite the relatively brief 7-10 day duration of drug delivery.
Surodex was directly compared against topical dexamethasone in a separate randomized, double-masked study of 60 cataract surgical patients conducted in Singapore by Tan, et al.2 One half of the patients were randomized to treatment with dexamethasone 0.1% eyedrops four times a day for 30 days postoperatively. The other half of patients received a single Surodex pellet at the conclusion of uncomplicated surgery followed by normal saline placebo eyedrops four times a day for 30 days.
Postoperatively, mean Kowa laser flare values were significantly lower in the Surodex treatment group compared with the topical steroid treatment group during the first two postoperative weeks (p <_0.01. mean="mean" cell="cell" and="and" flare="flare" scores="scores" as="as" judged="judged" by="by" masked="masked" slit="slit" lamp="lamp" examination="examination" were="were" slightly="slightly" lower="lower" in="in" the="the" surodex="surodex" treatment="treatment" group="group" but="but" not="not" statistically="statistically" significant.="significant." there="there" no="no" significant="significant" adverse="adverse" events="events" or="or" complications="complications" attributable="attributable" to="to" either="either" study.="study." specifically="specifically" instances="instances" of="of" elevated="elevated" iop="iop" that="that" persisted="persisted" beyond="beyond" pod="pod" _1="_1" possibly="possibly" reflecting="reflecting" short="short" duration="duration" drug="drug" administration.="administration." p="p">
FDA Phase III completed enrollment in September 1998 of 305 patients at 9 separate study sites. The final data will be submitted to the FDA this year. Worldwide, Surodex is being used in Mexico, Singapore, and China after passing regulatory requirements for each respective country. To date, more than 3000 total eyes have received the implanted delivery system.
This concept of a biodegradable intraocular drug delivery system can be extended to countless other drugs and potential ocular applications as well. Limited trials of a quinolone antibiotic delivery system for endophthalmitis prophylaxis have been done in Mexico and Singapore. Such products may become particularly important in third world settings where topical medications are not otherwise available following ocular surgery. A prolonged intraocular means of drug delivery may also prove to be essential for pharmacological treatments of retinal disorders such as diabetic retinopathy or macular degeneration in the future.
Whether administering antibiotic or anti-inflammatory medications, an ideal perioperative drug delivery system for cataract surgery would have the following attributes. It would demonstrate superior efficacy by providing an adequately high and prolonged drug level at the desired site. It would be safe and would confine the drug action to the desired intraocular location. It would be compatible with topical anesthesia and immediate vision. It would be short acting enough to diminish the risks from side effects or allergy, but long acting enough to obviate the necessity for postoperative topical therapy. Further studies are warranted to confirm whether the Surodex is able to provide most of these benefits.
In conclusion, on the basis of these two prospective randomized double masked studies, the dexamethasone drug delivery system appears to be a promising and possibly more efficacious alternative to topical steroids following uncomplicated cataract surgery. In addition, by reducing or eliminating the need for patient instruction and compliance, this system of drug delivery may ultimately prove to be a more patient friendly, physician friendly, and cost effective alternative as well.
Dr. Chang is clinical professor of ophthalmology at the University of California, San Francisco, and in private practice in Los Altos, California. He has no financial interest in this product.
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