Our understanding of the development and progression of posterior segment diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), noninfectious uveitis or central serous chorioretinopathy has never been better. This knowledge has led to the development of new drug targets and improvements to existing drugs, enhancing our ability to treat these patients and better predict outcomes. Great news! But questions still remain . . . is the effectiveness of these drugs being optimized? Are they being limited by their delivery within the eye, but not specifically to the site of disease? Are these drugs affecting non-target tissues?
Drug delivery to precise structures of the eye is a puzzler for the ages. Traditional routes of delivery, namely topical eye drops and intravitreal injections, are the current gold standards used for treating most ophthalmic diseases. Topical eye drops result in low bioavailability within the anterior chamber and negligible penetration beyond, meaning they are highly limited to any role in the management of posterior segment diseases. Intravitreal injections have revolutionized the treatment of retinal disease by allowing the vitreous to serve as a natural depot, slowly releasing drug. Again, great news, however, isotropic diffusion of drug to non-target regions and tissues can lead to undesirable consequences. In addition, the eye has unique barriers: An intact blood-retinal barrier can impede the transport of drugs from the vitreous to the choroid and retinal pigment epithelium, which may be a beneficial target for early treatment.
Considering what we know and the challenges of current drug delivery in treating patients with posterior disease, the suprachoroidal space (SCS) has been proposed as a potentially attractive site for drug delivery. Where is the SCS? The SCS is the space between the sclera and choroid that traverses the circumference of the posterior segment of the eye. Imagine drug delivery directly to the posterior segment, targeting the choroid, retinal pigment epithelium and retina with high bioavailability, while limiting drug contact to non-target regions . . . attractive indeed!
Bryce Chiang, Jae Hwan Jung and Mark R. Prausnitz from the Georgia Institute of Technology recently published a comprehensive review of drug delivery strategies within the SCS. They also explored current and potential clinical indications and the safety and efficacy of the approach. The manuscript, “The suprachoroidal space as a route of administration to the posterior segment of the eye,” appeared online on March 8, 2018 in Advanced Drug Delivery Reviews. The authors report the anatomy and physiology of the SCS, methods of access and drug kinetics. The paper provides evidence as to how the proximity of the SCS to the choroid has the potential to optimize drug delivery for posterior segment diseases because high bioavailability within the choroid (and potentially the retina) can be achieved. This technique may allow for a lower drug dose to attain comparable efficacy to traditional routes of administration. The compartmentalization of the SCS also limits drug exposure to non-diseased tissues, with the expectation of a more favorable side effect profile.
Dr. Igor Kozak, a clinical lead at the Moorfields Eye Hospital Centre in Abu Dhabi, who has a particular research interest in retinal pharmacology and drug delivery systems, comments: “The authors present an excellent review on anatomy and physiology of suprachoroidal space of the eye as well as pharmacology and clinical application of drug delivery into this compartment.”
“The report updates us on clinical trials with agents administered to suprachodoidal space and diseases to be potentially treated in this fashion,” he added.
“Drug delivery to the posterior segment is often done from the inside out – that is, from an intravitreal injection outward to the retina, RPE and choroid, but also to other parts of the eye like the lens and anterior segment. Drug delivery to the suprachoroidal space localizes drug between the sclera and choroid, from which the drug travels from the outside into the choroid, RPE and retina, with much less exposure to other parts of the eye,” explained Dr. Mark Prausnitz, study author.
The paper explores accessing the SCS ab interno surgical technique, by sclerotomy with subsequent micro-cannulation, or by microneedle injection to the SCS. While access to the SCS by sclerotomy and catheterization has been FDA-cleared, it is a surgical intervention that is not in clinical use.
Dr. Manish Nagpal, a vitreoretinal consultant at the Retina Foundation in Ahmedabad, India, agrees: “Theoretically, the suprachoroidal space seems to be ideal for injecting various drugs as the absorption would be enhanced.” He does, however, note the challenges of SCS drug delivery: “So far, the challenge has been to find a delivery which can be safely administered as an in-office procedure, by any retina specialist instead of only being given in a specialized setting.”
In addition to a thorough review of the existing literature, Dr. Prausnitz and his team at Clearside Biomedical have first-hand experience with drug delivery into the SCS.
Dr. Prausnitz explains: “While surgical techniques have been used to access the suprachoroidal space, the use of a microneedle makes suprachoroidal injections simple and reliable in the hands of a trained ophthalmologist. With a successful phase III clinical trial recently completed and two more phase III clinical trials underway at Clearside Biomedical, there could be products available to doctors and patients in the near future for delivery of steroids and other compounds into the suprachoroidal space that optimizes drug efficacy and minimizes side effects by targeting drugs to the choroid and adjacent RPE and retina.”
Dr. Kozak will be carefully watching for the upcoming results of the new surgical techniques to access the SCS, noting of the paper: “Of particular interest is microneedle injection system designed to safely deliver medicines into this virtual space. The reader is informed that several important advancements have taken place to investigate this therapeutic approach which we expect to become a popular therapeutic armamentarium for a myriad of ocular diseases.”
On the other hand, Dr. Nagpal has been watching this proposed change to drug delivery evolve, noting: “Various cannulas and needles in the past have been devised but require a lot of skill and technical expertise to safely insert in the right space and hence, this area has never become widely popular.”
“The concept of microneedle theoretically seems like a good solution and if it can be effectively and safely replicated in an office procedure setting, it may change the way we deliver drugs for various pathologies,” he added. This paper demonstrates that the SCS offers a novel route of administration to the posterior segment of the eye and provides great promise for improved drug targeting to sites of action in sclera, choroid and RPE. Microneedle injection into the SCS is receiving significant attention and is undergoing phase III clinical trials and optimized drug delivery strategies and formulations are the subject of ongoing research.