aspects. The most important aspect for the eye is the ability to deliver a drug to a site that is not directly accessible. This is an important element in suprachoroidal delivery because the microneedle is inserted at an accessible portion of the eye and the formulation is spread within the suprachoroidal space to an inaccessible region ­further back in the eye. The other important aspect is that a hollow microneedle allows more of a drug to be delivered in a single injection compared to other microneedle strategies. This is because a hollow microneedle simply serves as a conduit for delivery whereas in other scenarios the surface area or volume of the microneedle limits the amount of drug that can be delivered from a single insertion.

Fabrication of hollow microneedles can be challenging because an internal bore needs to be created within the structure and this may compromise the mechanical integrity of the microneedle. Hollow metal microneedles have been made from micromolding and etching techniques. These techniques can be used to make hollow silicon, nickel, and gold microneedles (Gardeniers et al. 2003; McAllister et al. 2003). Glass microneedles fabricated using micropipette pulling techniques have been shown to effectively insert and deliver into skin. Martanto et al. showed that in addition to microneedle insertion and infusion parameters, the tissue itself can be a limiting factor in how much volume can be delivered. Ex vivo experiments showed that partial retraction of the hollow microneedle aided in infusing fluid into the skin and reducing the compaction of skin that occurs at the site of insertion (Martanto et al. 2006). Hollow microneedles have also been shown to deliver insulin into human skin in vivo. Experiments on humans using hollow microneedles showed that delivering a bolus injection of insulin into the dermis were effective at reducing blood glucose levels (Gupta et al. 2009).

14.5  Discussion

Administration to ocular tissues using coated microneedles allows pinpoint delivery of drug at the site of insertion. Pinpoint delivery has both advantages and disadvantages depending on the goal of the delivery. The major advantage is that it allows precise targeting of the drug to a site with minimal exposure to the surrounding area. As an example, if there is an intrastromal infection within the cornea at a known location, a coated microneedle can deliver an antibiotic or antifungal drug directly within the stroma near the site and thus localize delivery to the affected area. However, in some cases, it may be beneficial to have targeted delivery to a larger region. In the case of a glaucoma drug targeted at the trabecular meshwork, it may be more advantageous to deliver the drug at different sites in the trabecular meshwork around the limbus. In such a case, a single coated microneedle would cover only a limited region of the trabecular meshwork and multiple coated microneedles may need to be inserted at different sites along the limbus. One of the major limitations of this approach is the dose that can be administered. The dose is limited by the surface area available for coating. As a result, optimization of the coating formulation and coating parameters become important factors.

An alternative to coated microneedles can be biodegradable polymer microneedles. These microneedles can encapsulate a drug within the volume of the microneedle. If mechanical and other properties of the microneedle permit a large percentage of the microneedle volume to be drug, then the dose that can be delivered by a single microneedle can increase significantly. However, these microneedles would need to be left inside the tissue in which they are inserted. This may not be feasible in all scenarios. An advantage of polymeric microneedles is that they can be designed to degrade slowly and, as a result, the drug can be released over a longer period of time than if the free drug was administered. This would be a major advantage, as the frequency of administration can then be reduced. Polymer microneedles have yet to be evaluated for ocular drug delivery and, as a result, their ability to insert and remain at the inserted site has yet to be determined. Once this is confirmed, they may be of interest for scenarios of extremely localized and targeted controlled release of drugs.

Hollow microneedles are convenient for back of the eye delivery since liquid formulations can be injected within the sclera or suprachoroidal space. A microneedle can be inserted in one site and the formulation can flow to cover a selected region of the back of the eye. This approach allows delivery of doses larger than what would be capable from single solid microneedles. Using only a single microneedle is particularly advantageous in the eye, as it avoids creating multiple openings in the eye. Parameters such as insertion depth, infusion pressure, and ­viscosity of the formulation become important in determining successful delivery and spread of injected formulation. Intrascleral drug delivery may be advantageous at forming a depot within the sclera that can provide sustained delivery. However, the limited capacity of the sclera to hold large volumes and long injection times may limit clinical use. Suprachoroidal delivery may allow for injection of larger volumes and more spread of the formulation within the back of the eye. Suprachoroidal delivery is also attractive because it deposits the drug just below the retinochoroidal surface which is the target for many back of the eye diseases.

Injecting fluids into the eye using a hollow microneedle may carry risks and complications that are more serious than simply inserting solid microneedles. These risks have yet to be evaluated in any formal safety study since hollow microneedlebased intrascleral and suprachoroidal delivery are still relatively new approaches to ocular drug delivery. However, injecting into the suprachoroidal space using larger needles and through the use of catheters has shown that injecting fluid into the space can be safe if the procedure is done with minimal trauma to the eye and especially the choroid (Olsen et al. 2006; Hou et al. 2009). There has been no study as of yet investigating the effect of injecting into the suprachoroidal space repeatedly. Further in vivo work is necessary to understand the safe conditions, under which these injections can be performed, and the associated risks.

Research on microneedles as a way to administer drugs into the eye is a novel concept that has been investigated only within the last few years. There are a variety of microneedle delivery strategies and depending on the disease and target one particular microneedle delivery strategy may be more advantageous than another. The initial research has shown that microneedles offer a variety of options for targeting

tissues of the eye in a minimally invasive way. There is some, though limited, in vivo data on the use of microneedles. Further research needs to focus on translating successful­ in vitro results into in vivo scenarios and understanding the pharmacokinetics of drugs delivered through these routes. Additional safety data will also be necessary to show that the minimally invasive method translates into a safe delivery method in vivo. Finally, there are currently no reported studies that have tested microneedle-based administration for the treatment of a disease in an animal model. This kind of work will be critical in demonstrating that the targeting capabilities of microneedles can result in improved performance and/or safety.

14.6  Conclusion

One of the key challenges to effective ocular drug delivery is to target the delivery to a specific tissue or region of the eye. The work discussed in this chapter has shown that microneedles are versatile and capable of targeting regions of the eye to deliver drugs in a variety of scenarios. Two types of microneedles, coated solid microneedles and hollow microneedles, have been shown to effectively deliver small molecules, macromolecules, and particles into ocular tissues. These microneedles have enabled intrastromal delivery into the cornea, intrascleral delivery, and suprachoroidal delivery in a minimally invasive manner. This capability stems from the match between the sub-millimeter microneedle size and the similar dimensions of the ocular tissue barriers. The early research on microneedles shows that these routes of administration may be beneficial for treating a variety of diseases of the eye.

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