Drug delivery to the eye: current trends and future perspectives

Drug delivery remains one of the unmet needs identified in ophthalmology

The eye is a direct extension of the CNS. The clarity of its different structures and media and its exposure outside the body create ideal conditions for local delivery of drugs. In appearance, the eye seems easily accessible but delivering drugs to the eye remains one of the major challenges of modern ophthalmology. The ocular surface forms a complex association of secreted fluid layers with the cornea to protect the eye from outside aggression. Besides high resistance of the tight-junction corneal epithelium, the structure of the cornea formed by a succession of lipidic and hydrophilic layers itself limits transcorneal penetration of compounds. The eye, similar to the brain, is protected from the systemic circulation by tissue and cell barriers: the tight-junction of the ciliary body epithelium; the retinal pigment epithelium and endothelial cells of the iris; and the retina. Therefore, anatomic and dynamic barriers for drug penetration into the eye tissues exist.

The eye is artificially divided into two major parts. The anterior segment comprises the ocular surface, the cornea and anterior chamber, the iris and ciliary body, and the lens. The posterior segment comprises the vitreous, the retina, the choroid and the optic nerve head. This artificial division is actually well adapted for ocular pharmacology and drug delivery, since methods and routes of administration differ upon the targeted eye segment.

Drug delivery to the anterior segment of the eye

Schematically, to deliver drugs to the anterior eye segment, topical instillation are efficient when using appropriate formulations. Indeed, only weakly acidic, basic or amphiphilic molecules can theoretically follow a transcorneal penetration. In practice, preservatives such as benzalokonium chloride act as permeates, destabilizing the corneal junctions and subsequently enhancing ocular drug penetration [1]. After topical instillation, the bioavailability is less than 5% due to the rapid clearance of drug from the surface. Once in the anterior chamber, the half-life of the drug is usually short due to the recycling of the aqueous flow. Years of research, mostly conducted by the industry, have been dedicated to improving the tolerance and reducing the frequency of drop instillations in order to gain patient compliance and increase drug bioavailability. Drops are used to lower ocular pressure in glaucomas and to reduce inflammation in uveitis, both of which chronic diseases requiring long-term treatment and good treatment observance.

Formulations have been designed to increase the time residency at the ocular surface, to enhance the ocular penetration of hydrophobic compounds (limited to the corneal epithelium), and to improve the long-term tolerance [2]. More recent advances include hydrogels, microparticles, nanoparticles, microemulsions [3], liposomes [4] and other colloidal systems [5]. Inserts placed in the cul-de-sac have a low tolerance, restricting their clinical application to the slow release of mydriatic agents in preparation for ocular surgery [6].

After topical instillation, besides transcorneal delivery, a transscleral passage was shown to appear for hydrophilic molecules of higher molecular weight. The idea that even proteins could be delivered locally is, thus, emerging [7]. This pathway can be used not only through drug instillation, but also after subconjunctival injections of high molecular weight compounds (up to 25 kD). Physical methods such as transscleral iontophoresis were also developed more than 15 years ago to enhance the ocular delivery of charged, low molecular weight compounds into both the anterior and posterior segments of the eye through this transscleral pericorneal pathway. Systemic administration of methylprednisolone to reverse corneal graft rejection [8] was shown to be effective and could be registered for the delivery of dexamethasone in the treatment of anterior uveitis, limiting the frequency of drug instillation for several days [9].

Drug delivery to the posterior segment of the eye

The more striking and revolutionary advances in medical ophthalmology concern the treatment of diseases affecting the posterior segment of the eye. For years, ophthalmologists were following the progression of age-related macular degeneration (AMD) and other retinal blinding diseases without any therapeutic options. In the early 2000s, liposomal verteprofine (Visudyne^®; Novartis, Switzerland), injected systemically was coupled to local infrared laser therapy to close abnormal choroidal neovessels complicating AMD [10]. A few years later, anti-VEGF agents were approved for the treatment of wet AMD using repeated intravitreous injections [11], begining a new era. Retina specialists realized that injections into the vitreous, limited until then to the treatment of severe intraocular infections, were feasible and well tolerated. Once in the vitreous, the systemic diffusion of the compound is limited, opening new opportunities for biotherapies [12] and the development of ocular drug-delivery systems for sustained release. Indeed, today one of the first unmet recognized needs in ophthalmology is to reduce the requirement for frequent intraocular injections. Preceding industrial developments, ophthalmologists used off-label drugs for intraocular administrations, which contained inappropriate excipients without real evaluation of their safety and efficacy. For example, intravitreous injection of triamcinolone acetonide has entered into clinical practice; it could slow the commercialization of the dexamethasone PLGA implant (Ozurdex^®, Allergan, CA, USA), approved for the treatment of macular edema secondary to vein occlusion and for non-infectious uveitis, particularly because of cost issues [13]. The non-biodegradable implant of fluocinolone acetonide (Retisert^®, Bausch and Lomb, NY, USA) was approved in 2005 for the treatment of severe uveitis, releasing steroids in the eye for more than 2 years. A reduced size of this implant, allowing minimally invasive implantation was just approved for the treatment of diabetic macular edema in the UK (Iluvien^® Alimera Sciences Inc., GA, USA). Whatever their method of delivery, corticosteroids are associated with frequent and potentially severe side-effects such as glaucomas. Now that approved drug-delivery systems are available for the sustained release of low doses of corticosteroids into the eye, ophthalmologists should avoid using off-label inappropriate formulations.

So, what is next in this rapidly developing area?

New biodegradable polymers for implants or particulate systems are emerging, allowing for the long and sustained release of active compounds (over several years), but questions of long-term toxicity of any degradation product on the retinal pigment epithelial cells remain unanswered. Retinal pigment epithelial cells engulf any debris since they have high phagocytic capacities, but the consequences of such accumulation on their specific phagocytic activity (photoreceptor outer segments) should be taken into account before injecting polymers into the vitreous cavity. Of further interest are the novel routes of administration, such as the suprachoroidal route [14]. Compounds or polymers can be easily introduced using a minimally invasive surgical procedure towards the macula without any retinal detachment [15]. In the suprachoroidal space, polymeric devices should not induce any long-term potential toxicity on retinal cells [16]. Another perspective for protein delivery to the posterior segment of the eye is gene therapy [12]. Viral vectors have been widely used for gene replacement in animal models of inherited retinal dystrophies as well as in clinical trials [17]. Viral gene therapy is still under development for the sustained production of secreted proteins, but transfection of retinal cells raises safety issues since viral particles are found in the brain after intraocular injection. More promising are the development of non-viral gene strategies [18] and of encapsulated cell intraocular implants (Neurotech, Inc., RI, USA) [19].

In the future, one can imagine that more targeted delivery to specific retinal cells will be achieved using a combination of new surgical techniques and instruments associated with drug or gene delivery [20]. Finally, work remains to be done to further understand and modelize pharmacokinetics of the posterior segment of the eye and to unravel the complexity of ocular barrier structures and regulations. Without this basic knowledge, no real breakthrough could be made in the field of ocular drug delivery.