microparticle suspension, demonstrating that disruption of the collagen structure allowed microparticle infusion within the sclera. The second approach involved co-injecting hyaluronidase, a dispersive agent known to help injectable formulations flow through densely packed tissues such as the skin, for which it has FDA approval. Microparticles were also successfully administered using this approach. As a result, incorporation of hyaluronidase into a suspension may be a feasible way to deliver controlled-release microparticle formulations within the sclera for drug delivery to the back of the eye (Jiang et al. 2009).

14.3.3  Suprachoroidal Delivery Using Hollow Microneedles

For treating diseases of the back of the eye that involves targets such as the choroid and retina, it would be beneficial to deliver the drug as close as possible to these tissues. In addition, it would be beneficial to localize the drug to these regions to maintain high levels of drug over time without exposing other eye tissues to the drug. The complication with this approach is that the choroidal and retinal tissues cover a large region of the back of the eye and much of it is inaccessible directly. This is especially true for treating the macula in cases of neovascular AMD. If a method of administration could allow direct injection of a formulation in close proximity to the retinochoroidal tissues from a site that is easily accessible, it would provide a much needed advantage over currently practiced methods. If a formulation can be injected in a circumferential manner so that it flows from an anterior location in the eye to the posterior near the macula while bathing the retinochoroidal tissue, it would also allow large doses to be delivered, as well as cover a large portion of the back of the eye.

One approach to accomplish this circumferential delivery would be to inject a formulation into the suprachoroidal space. Suprachoroidal delivery refers to a relatively new route of administration to deliver drugs to the back of the eye. Unlike many approaches, this approach attempts to target delivery not within tissues or media of the eye, but to deliver a drug formulation between two tissue layers. The suprachoroidal space refers to a space in the eye that is created when there is fluid buildup between the sclera and choroid layers of the eye (Emi et al. 1989; Krohn and Bertelsen 1997). Figure 14.11a shows an idealized cartoon of what delivery into this region would look like. This region is particularly attractive because a drug in the suprachoroidal space is in direct contact with the choroid, which is adjacent to the retina (Patel et al. 2010). These two tissues are the targets for many diseases such as AMD, uveitis, and diabetic macular edema, which can lead to blindness. A drug delivery method that can reliably deliver into this region could provide a more targeted approach to treat these diseases.

Recently, researchers have shown that there are several ways to take advantage of this region and access the space. These methods, however, are invasive and may not be suitable for long-term clinical therapy of chronic back of the eye diseases. They involve the use of catheters or implants that are surgically placed in the eye to access the suprachoroidal space (Einmahl et al. 2002; Gilger et al. 2006; Olsen et al. 2006; Kim et al. 2007). A hollow microneedle is an attractive alternative to inject formulations

Fig. 14.11  Suprachoroidal delivery. (a) An idealized image of the anatomy of the periocular tissues near the insertion site before and after suprachoroidal injection. Image of the eye was adapted from National Eye Institute, National Institutes of Health, with permission. (b, c) Brightfield images of a cross-section of a frozen pig eye showing (b) normal ocular tissue and (c) showing the delivery of sulforhodamine B (pink) between the sclera and choroid (i.e., in the suprachoroidal space). Scale bar: 500 mm. Reproduced from Patel et al. (2010) with permission from Springer Science

into the suprachoroidal space, because it offers a minimally invasive route. If a hollow microneedle can access the suprachoroidal space, it may provide micron-scale targeting of the sclera and choroid interface in a minimally invasive procedure.

Hollow microneedles have been shown to target the suprachoroidal space and deliver fluids and particles within the suprachoroidal space of rabbit, pig, and human eyes. Hollow microneedles inserted ex vivo into whole pig eyes showed that a sulforhodamine solution could be injected into the suprachoroidal space. The space could be selectively targeted, causing the sclera–choroid interface to expand and fill with fluid (Fig. 14.11b, c). Volumes up to 35 mL could be injected into this space ex vivo and the delivery of the solution looks to be well targeted to the suprachoroidal space. Additional experiments revealed that particles up to 1 mm in diameter could be delivered into the suprachoroidal space of rabbit, pig, and also human eyes. Figure 14.12 shows the delivery of particle suspensions in

Fig. 14.13  A graph showing the effect of infusion pressure and microneedle length on the success rate of suprachoroidal delivery for (a) 20 nm, (b) 100 nm, (c) 500 nm, and (d) 1,000 nm particles in porcine eyes. A total of five infusions were attempted at each condition. Overall, increasing microneedle length and increasing infusion pressure increased the delivery success rate for all particle sizes. Reproduced from Patel et al. (2010) with permission from Springer Science

these different species (Patel et al. 2010). This shows that a hollow microneedle is versatile enough to deliver fluids and particles into the suprachoroidal space of eyes in three different species.

Delivery of particles into the suprachoroidal space offers the potential for controlled or sustained delivery to the chorioretinal surface. If the parameters necessary for particle administration into this space using microneedles can be determined, then a minimally invasive delivery method and device can be designed. Detailed experiments were performed on pig eyes ex vivo to determine the necessary parameters for delivering particles of 20, 100, 500, and 1,000 nm in diameter into the suprachoroidal space. These studies showed that as the particle size increased, the applied pressure and microneedle length were critical parameters for achieving realiable suprachoroidal delivery into pig eyes ex vivo (Fig. 14.13). The hypothesis for this is that suprachoroidal administration using a hollow microneedle is ­performed by inserting the microneedle

Fig. 14.14  Images showing the effect of particle size on particle distribution in the eye. Fluorescence microscopy images of tissue cryosections show the delivery of (a) 20 nm particles and (b) 1,000 nm particles into the suprachoroidal space of porcine eyes ex vivo. The images show that 20 nm particles can spread in the suprachoroidal space and within the sclera. However, 1,000 nm particles are primarily in the suprachoroidal space. The insets show a magnified view of the insertion sites, which are indicated by arrows. Scale bar: 500 mm. Reproduced from Patel et al. (2010) with permission from Springer Science

to the base of the sclera as opposed to directly inserting all the way into the suprachoroidal space. As a result, the initial barrier that must be overcome is movement of particles from the base of the sclera into the suprachoroidal space or choroid. This is governed by the anatomy of the sclera and the issues associated with intrascleral delivery also apply here as well. It was significantly easier to deliver particles less than 500 nm vs. larger than 500 nm in diameter (Patel et al. 2010).

This hypothesis was further confirmed by imaging the delivery of different-sized particles within the ocular tissues. The effect of collagen fiber spacing in the sclera discussed above suggests that particles of 20 and 100 nm should be able to spread within the sclera as well as the suprachoroidal space, whereas particles of 500 and 1,000 nm should localize exclusively in the suprachoroidal space. Figure 14.14 shows the spread of 20 nm particles and 1,000 nm particles under identical injection conditions within the layers of the eye. As expected, the smaller particles spread