Chapter 14

Targeted Drug Delivery to the Eye Enabled by Microneedles

Samirkumar R. Patel, Henry F. Edelhauser, and Mark R. Prausnitz

Abstract  Drug delivery targeted to specific tissues within the eye represents an important advance over conventional methods of topical and injectable delivery that have poor specificity for particular ocular tissues requiring therapy. This level of intraocular targeting can be achieved using microneedles, which are solid and hollow­ needles of micron dimensions. Microneedles can selectively target intraocular tissues by delivering drug formulations within the cornea, sclera, and suprachoroidal space in a minimally invasive manner. Intrastromal delivery in the cornea, intrascleral delivery, and suprachoroidal delivery using microneedles have been shown to deliver small molecules and macromolecules, as well as nanoparticles and microparticles. Delivery strategies have employed a variety of microneedle designs including coated microneedles that administer solid formulations and hollow microneedles for injection of liquid formulations. The work reported in this chapter highlights the capabilities of microneedles to provide targeted delivery to the eye in a minimally invasive way through in vitro and in vivo animal studies.

14.1  Introduction

On the one hand, local drug delivery to the eye is facilitated by the fact that the eye is one of the few organs that is visible and directly accessible from outside the body. However, the direct exposure of the eye to the outside environment results in

M.R. Prausnitz (*)

School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive, Atlanta, GA 30332-0100, USA

e-mail: prausnitz@gatech.edu

H.F. Edelhauser (*)

Emory University Eye Center, Emory University, 1365 Clifton Road NE, Atlanta, GA 30332, USA

e-mail: ophthfe@emory.edu

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 331 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_14,

© American Association of Pharmaceutical Scientists, 2011

the eye possessing natural barriers that prevents drugs from effectively penetrating the outer surface of the eye to reach their target intraocular sites. A few of these barriers include the complex nature of the tear fluid, the reflex of blinking and associated tear fluid drainage, clearance from lymphatic and blood flow within the conjunctiva, and diffusion-limited transport across the epithelial barriers of the cornea and conjunctiva (Koevary 2003; Urtti 2006). As an additional constraint, any pharmacological treatment procedure should not hinder the natural function of the eye. This primarily means that any drug formulation or method of delivering that formulation should not hinder the ability of light to reach the retina. Barriers and requirements such as these make effective pharmacological treatment of eye diseases a challenging endeavor.

One of the most challenging aspects of drug delivery to the eye is to provide sustained and targeted delivery in a minimally invasive way. Many of the most prevalent vision-threatening diseases, such as age-related macular degeneration (AMD), glaucoma, uveitis, and diabetic retinopathy, are chronic conditions that require continued therapy to maintain or improve vision (Friedman et al. 2004). This is especially true for diseases of the back of the eye, because access is more limited.

14.2  Current Methods of Drug Delivery to the Eye

Current focus of research and development of ophthalmic devices and formulations has been aimed at dealing with sustained or controlled drug delivery over time. A number of commercial products have recently been marketed that can provide drug delivery for a period of months to years. Examples include Medidur®, which delivers fluocinolone for 18 or 36 months to treat diabetic macular edema, Retisert®, which also delivers fluocinolone for approximately 32 months to treat uveitis, Vitrasert®, which delivers gancyclovir for up to 8 months to treat cytomegalovirus retinitis (Kuppermann 2007) and Ozurdex® (formerly Posurdex®), which delivers dexamethasone for 6 months to treat macular edema (Chang-Lin et al. 2010). Many of these products are implants that are placed in the vitreous and, in some cases, are attached to the globe so that the drug formulation is released into the vitreous over time (Yasukawa and Ogura 2010). Implants such as Medidur®, Vitrasert® and Retisert® are nonbiodegradable and have to be removed once the drug has been fully released from the device (Kuppermann 2007). Ozurdex® is a biodegradable implant that does not have to be removed at the end of treatment (Kuno and Fujii 2010). These devices enable sustained or controlled delivery and help maintain drug levels in the eye without frequent administration.

All the above-mentioned devices, however, suffer from poor targeting to the tissues that need treatment for the most common diseases of the back of the eye. As an example, even though the complete pathophysiology of wet-AMD is still uncertain, the affected tissues are the choroid and retina, not the vitreous (Janoria et al. 2007; Bressler 2009). Yet, these devices are all aimed at delivering drugs directly to the vitreous. Since the vitreous humor is a gel-like medium that fills a large volume of the eye, the drugs that are released into the vitreous come into contact with other

nontarget tissues of the eye as well. This lack of targeting is generally a concern for all approaches that release drugs into the vitreous, including intravitreal injections that have become a common method to deliver drugs to the back of the eye (Peyman et al. 2009). In addition, the large volume of the vitreous dilutes the released drug. This implies that drug delivered intravitreally needs to be of a higher dose in order to maintain a therapeutic level than if it were delivered in a targeted way to tissues such as the retina and/or choroid.

These two issues are particularly problematic for the above devices because they release steroids that come in contact with the lens and cause side effects such as cataracts (Ozkiris and Erkilic 2005). Although these devices have helped to address one of the key goals of drug delivery, i.e., sustained delivery, they have not targeted that delivery particularly well to the desired target tissues. In addition, these approaches are invasive. Implants are most often surgically placed and, if they need to be removed, an additional surgery is required.

Targeting drug delivery to the front of the eye has similarly not received sufficient attention. As an example, many glaucoma drug therapies require a drug to act on the ciliary body or the trabecular meshwork to decrease production or increase outflow of aqueous humor, respectively (Lee and Higginbotham 2005). Yet, most drugs are administered using drops on the surface of the eye. Although, drops are a convenient method of application that is noninvasive, they expose a large surface of the eye to the drug. In addition to delivering a fraction of the drug to the desired region of the eye, much more of the drug is administered to other parts of the eye and even more of it is removed from the eye to other parts of the body through the nasolacrimal duct and absorption by subconjunctival vessels (Jarvinen et al. 1995). Once again, this applies not just to topical drops but for any method that administers drugs to the corneal surface. As a result, topical drug delivery is not very effective at targeting the drug to the desired location within the eye for glaucoma therapy.

In general, a method that is effective at targeting localizes the drug at high concentration in or near the target eye tissue while minimizing exposure of other tissues so as to avoid side effects and complications. When examining the current approaches for ocular drug delivery, many of them are not designed with this goal in mind. These approaches can be roughly divided into two strategies. The first is either a periocular or superficial strategy to place the drug on the outer surface of the eye by administration methods such as drops, injections, or implants. In many cases, the therapeutic target is not on the outer surface of the eye and, as a result, the drug needs to diffuse across the cornea and/or sclera to intraocular tissues to be effective (Ghate et al. 2007; Gaudana et al. 2010). Intravitreal strategies deliver drugs directly into the vitreous and are thereby effective at overcoming barriers that prevent getting drug into the eye. However, the drug then spreads throughout the vitreous and this exposes multiple nontarget tissues to the drug as it moves toward the target site (Krohne et al. 2008; Cheng et al. 2009).

Many of the tissue targets for diseases of the eye are less than 1 mm beneath the globe of the eye. These include the corneal stroma, the ciliary body and trabecular meshwork for front of the eye diseases and the choroid and retina for back of the eye diseases (Lee and Higginbotham 2005; Gaudana et al. 2010).