Optimal drug delivery into the posterior segment remains an important challenge in the management of the many diseases affecting the retina. Current drug delivery options are largely limited to intravitreal injections, which can be associated with complications due to their invasive nature. Topical delivery can be inefficient, while systemic administration is not a viable option as large doses are needed to reach the necessary intraocular concentrations. Intraocular implants and gene therapy are additional alternatives. And until there is an optimal drug delivery system for posterior segment conditions, continued research and improvement is needed.
Based on a presentation by Dr. Arto Urtti, University of Helsinki, Finland, called “Posterior Segment Pharmacokinetics: Connecting the Dots”.
Recently, Dr. Arto Urtti and colleagues from the University of Helsinki, Finland, provided a synopsis of posterior segment pharmacokinetics. Analyzing literature from studies in rabbits and humans, the authors showed that volume of distribution (Vd) was almost constant for all the compounds analyzed. For drug clearance following intravitreal dosing, Dr. Urtti explained that there is a
very big variation, and this is highly dependent on the nature of compound studied. Proteins have much lower clearance values (longer half-lives) and reduced inter-protein variability, as compared to small molecules which have higher clearance (up to 50 folds higher) owing to higher permeability through the blood-retinal barrier. Dr. Urtti explained the critical importance of other key pharmacokinetic parameters in vitreal drug disposition, such as drug binding to the vitreous, melanin binding and melanosome permeability.
“Blood-retinal barrier permeability and melanin binding are the most important factors in posterior segment pharmacokinetics of small molecules,” concluded Dr. Urtti. He also added the for biologicals, diffusion in the vitreous and penetration to the retinal layers may also be important.
Based on a presentation by Dr. Rocio Herrero-Vanrell, Faculty of Pharmacy, Complutense University, Spain, called “Microparticles as Therapeutic Tools in Retinal Diseases”.
There is a therapeutic gap in delivering drugs to the posterior that needs to be addressed – and now, novel strategies to optimize retinal drug delivery are being developed. Dr. Rocio Herrero-Vanrell from the Faculty of Pharmacy, Complutense University, Spain, shared key insights into the state-of-the-art drug delivery options to the posterior segment. According to Dr. Herrero-Vanrell, available drug delivery options for posterior segment include nanoparticles (1-1000nM), microparticles (1-1000µm) implants (>1mm) and depot systems. “However, the right choice of appropriate drug delivery system depends on the target site, the ophthalmic disease and the anticipated duration of treatment,” he said.
Microparticles have unique physicochemical properties which make them good options for posterior segment drug delivery. According to Dr. Herrero-Vanrell, microparticles can be administered as conventional injections, using conventional 30-32G needles. In addition, they are also useful for long term delivery and, depending on their size, they exhibit different drug delivery profiles. Furthermore, it is possible to include more than one active substance in the same formulation of microparticles, and they can indeed behave like an implant because they can aggregate at the site of administration.
Dr. Herrero-Vanrell explained that microparticles exist either as microcapsules or microspheres and can be administered via the periocular, subconjunctival, subretinal and intravitreal routes. Several biodegradable polymers are available to prepare microparticles, however, polylactic glycolic acid (PLGA) is preferred because of its high biocompatibility.
In rats treated with spironolactone PLGA microspheres, sustained release of spironolactone has been shown, together with high intravitreal concentrations and excellent, dose dependent morphological and functional tolerance.
“Biodegradable microspheres for intraocular drug delivery represent an alternative to repeated intraocular injections, no surgical procedures are needed and injections can be reformed through small gauge needles,” concluded Dr. Herrero-Vanrell. “They are able to release the drugs for several weeks or months, are able to encapsulate more than one drug and are therefore useful for multifactorial diseases, and can be used for personalized therapy,” he explained.
Based on a presentation by Dr. Einar Stefansson, University of Iceland, called “Cyclodextrin Nanoparticle Eye Drops for Retinal Diseases”.
It is well established that conventional eyedrops do not provide significant intra-retinal drug concentrations and are ineffective in retinal diseases. However, Dr. Einar Stefansson, from the University of Iceland, explained that for eye-drop based drug delivery, the molecule must not only be lipophilic to penetrate the eye wall, but must also be soluble in aqueous eye drop and tear film. Finding the optimal ocular drug delivery system means overcoming these limitations of conventional eye drops.
According to Dr. Stefansson, these obstacles have been overcome using cyclodextrin nanoparticles. Cyclodextrin reversibly binds to lipophilic drug molecules making them soluble in water. These cyclodextrin-drug complexes aggregate to form nanoparticles of approximately 100nm in diameter, which adhere to the eye to provide sustained release. Dr. Stefansson noted that the drug molecules are gradually released into the tear film and then into the eye in a process that is reversible.
Current published literature has shown that cyclodextrin nanoparticle eye drop suspensions increase solubility of lipophilic drugs by 10- to 100-fold, compared to conventional eye drops. In addition, they allow extended duration of delivered drugs.
Dr. Stefansson also discussed findings from a study that measured the concentration of dexamethasone in tear film after topical administration in rabbits and humans, using conventional versus nanoparticle-based delivery. The study showed sustained high dexamethasone concentrations with nanoparticles in both rabbits and humans. In addition, eye-tissue concentrations at two hours post-administration remained significantly higher with nanoparticles. These are supported by data from clinical trials in humans.
“Contrary to what has been the dogma since the beginning of time, it is possible to deliver drugs to the retina with an eyedrop,” concluded Dr. Stefansson.
Based on a presentation by Dr. Ronald Buggage, Eyevensys SAS, Paris, France, called “Viral and Non-viral Gene Delivery for Retinal Diseases”.
“The Eyevensys non-viral gene therapy ocular delivery platform overcomes the disadvantages of viral and non-viral vectors to offer a novel approach for the expression of therapeutic proteins in the back of the eye.”
Gene therapy is one approach to deliver drugs to the retina. According to Dr. Ronald Buggage of Eyevensys SAS, Paris, France, gene therapy involves the transfer of therapeutic genetic material (DNA or RNA) via viral or non-viral vectors to correct or modify the expression of genes influencing a disease process.
Gene therapy works either by replacing a disease-causing gene with a normal gene, inactivation of a disease-causing gene by the introduced new gene, or as witnessed more recently through gene editing, by cutting out an abnormal gene – especially when the protein products of that gene are causing structural defects.
Dr. Buggage says the eye is an ideal target for gene therapy for several reasons. Firstly, the globe is enclosed and relatively separate from the rest of the body and is an immune privileged space. In addition, retinal cells do not divide, therefore genes delivered have high chances of long-term expression. Furthermore, the small size of the retina means that small doses of vectors are needed, and outcomes can be easily monitored non-invasively. Another important reason is that the genetics of many inherited retinal diseases are well described, and suitable animal models are available.
Dr. Buggage also highlighted that ocular gene therapy is not only for inherited retinal diseases: Current data shows that age-related macular degeneration (AMD) remains the number one indication for ocular gene therapy. Viral vectors are the most commonly used vectors and, as noted by Dr. Buggage, “will likely remain the preferred gene therapy vector for inherited retinal diseases, with future generations of engineered viral vectors expected to show fewer safety concerns”.
“Non-viral vectors are a promising tool for sustained ocular drug delivery that may facilitate the development of new treatments for the posterior segment. The Eyevensys non-viral gene therapy ocular delivery platform overcomes the disadvantage of viral and non-viral vectors to offer a novel approach for the expression of therapeutic proteins in the back of the eye,” concluded Dr. Buggage. “The EYS606 [an Eyevensys lead product], being evaluated for the treatment of non-infectious uveitis will further clarify the risks and potential benefits of electro-transfer for non-viral gene delivery platforms.”
Editor’s Note: PIE Magazine Issue 07 was distributed at the Joint EURETINA-ESCRS 2018 Congress, held in Vienna, Austria. Reporting for this story, “Gene and Drug Delivery for Retinal Diseases: What is Next?”, also took place at EURETINA-ESCRS 2018.
