(Kim et al. 2007a, b). But, device implantation in this latter site can be more difficult than in the sub-Tenon’s space. Moreover, it has not yet been demonstrated that it can be used for long-duration systems.

1.3.3  Location of the Target Tissue

In most cases of posterior ocular disease, the target tissue is in the retina and/or choroid. Drug delivery to these tissues has been demonstrated in animals from a number of sites of administration, as discussed earlier but, the most productive and successful site for administering a drug delivery system, from a commercial point of view, is the vitreous.

The vitreous, being chamber of significant volume (ca 3 mL in man), is superior to other ophthalmic tissues in its flexibility to hold drug delivery systems of different designs, sizes, and shapes; these devices may be either degradable or nondegradable. But, as mentioned earlier, there is a small, but significant, chance of detaching the retina or causing endophthalmitis by this route. In addition, care must be taken to avoid blocking the field of vision, which begins roughly 5 mm in from the pars plana, toward the central line of vision. Also, if the device or suspension of drug or microspheres touches the lens – even briefly – a contact cataract may occur.

It should be kept in mind when designing a drug delivery device, that although the vitreous will support relatively large devices (e.g., 5 × 3.5 × 5 mm sutured to the sclera), the incision or injection should be as small as possible, in order to limit leakage of vitreous and to minimize the chance of retinal separation and/or infection. The incision is made through the pars plana region because this entry point is devoid of retinal tissue.

The vitreous may not be the best place to locate a drug targeting the optic nerve (e.g., a neuroprotective). For this target, the retrobulbar and sub-Tenon’s routes should be compared to intravitreal dosing by PK evaluation. If either of the latter locations deliver sufficient drug to the target, they should be preferred over puncturing the vitreous.

Occlusions of the CRVO may be treatable from a number of sites of administration including oral aspirin, oral or intravenously administered anticoagulants and fibrolytic agents, oral and intravenously administered anti-inflammatory agents, and intravitreal administration of a steroid, tissue plasminogen activator, or bevacizumab. It is a common practice to use topically or intravenously administered glaucoma agents to treat CRAO. However, the success of decreasing ocular pressure for this purpose is unclear (Arnold et al. 2005; Hazin et al. 2009). Better therapies are needed. The traditional CRAO therapy is to use intravenous acetazolamide to reduce intraocular pressure, along with anterior chamber paracentesis. More recently, it has been observed that the use of fibrinolytics appears to be more useful; if treated in the first few hours of onset of the occlusion, intravenous-administered fibrinolytic, such as tissue plasminogen activator, can be effective. Alternatively, urokinase has been administered through a microcatheter placed in the proximal segment of the ophthalmic artery (Schumacher et al. 1993; Koerner et al. 2004; Arnold et al. 2005; Hattenbach et al. 2008).

1.3.4  Potency of the Drug

The potency of a drug is another factor that impacts the design of a drug delivery system. If a drug is highly potent, then it can be delivered for months or years from a miniscule device. In contrast, if a high concentration of a drug is required at the receptor for efficacy, then there will need to be a trade-off between the size of the device and the duration of delivery. For example, the intravitreal device, Vitrasert® delivers ganciclovir from a coated tablet-core containing about 4.5 mg of ganciclovir and delivers an effective dose for a period of 5–8 months (Dhillon et al. 1998). The device dimensions are approximately 5 × 3.5 × 5 mm, after the surgeon manually adjusts the size. In contrast, Retisert™ contains 0.59 mg of fluocinolone acetonide – a medium to high potency corticosteroid – which delivers 0.3–0.6 mg/day for about 30 months and dimensions of this device are 3 × 2 × 5 mm (Hudson 2005; Miller et al. 2007).

A much smaller intravitreal device, Iluvien,® has completed clinical studies for the treatment of diabetic macula edema (DME) and an NDA has been submitted. Fluocinolone acetonide has been loaded into a tiny tubular device, which is injected through the pars plana and into the vitreous using a 25-gauge inserter; the device –a mere 3.5 × 0.37 mm cylinder – delivers drug for up to 3 years (Ashton 2009).

Potent drugs or, drugs which are not particularly potent, may be delivered by a novel ­phase-transition injector, which can deliver a substantially larger payload through a 27–30-gauge needle (Marsh et al. 2006). Inside a rapid-heating chamber, a drug delivery formulation is melted and injected into the vitreous where it “balloons” and rapidly solidifies to form a long-duration system. Preliminary toxicology studies have shown this system to be safe.

1.3.5  Need for Continuous or Pulsatile Delivery

It is well known that some receptors in the body are subject to tachyphylaxis – a decrease in the response to a drug after closely repeated doses. For example, decongestants (e.g., phenylephrine hydrochloride) will induce this response, when used continuously to treat nasal congestion; indeed, the rebound congestion may be quite severe.

There is evidence that some ophthalmic receptors may demonstrate tachyphylaxis (Chan et al. 2006; Forooghian et al. 2009). However, all of the commercial drug delivery systems are designed to deliver continuously. These systems are effective to some degree or they would not have had successful clinical trials or have been approved by regulatory bodies. Could these systems be more effective if they delivered drug in pulses? And, if so, how might a system be designed to deliver a pulsed dose?

One very innovative and interesting pulse-delivery system has been designed to release drug from gold-coated holes in a microchip via radio signal (Santini et al. 1998).

Another novel system is an implantable MEMS-activated miniature pump with a refillable drug reservoir, which is currently being commercially explored for ocular use; this device might be used to deliver either a continuous or pulsatile dose of a soluble or suspended drug on demand (Ronalee et al. 2009).

Drugs such as Lucentis and Macugen are currently delivered by intravitreal injection once every 4–6 weeks, despite the fact that their half-lives are far shorter than this periodic administration. Surely, the reason for selecting this dosing regimen is related to a balance between a need to minimize adverse effects of penetration into the vitreous while maintaining significant efficacy. But, is this choice of dosing interval the serendipitous equivalent of pulsatile delivery? Time will tell whether the continuous delivery of a Lucentis, in the effective range, will be found to be superior or inferior in efficacy, when compared to the current 4–6 weekly regimen.

1.3.6  Duration of Drug Delivery Necessary to Induce and Maintain Efficacy

A drug should only be administered as long as needed to treat the underlying disease state. So, for treatment of endophthalmitis, occlusions, or nonrecurring inflammation, a relatively short-duration drug delivery system may be sufficient. Since treatment of these maladies is likely to be for several days or perhaps a few weeks, the system should be biodegradable (or bioerodible) rather than nondegradable; ideally, the excipients should disappear entirely within a few days after the drug is gone.

For treatment of most other blinding diseases, a continuous or pulsed dose over long periods (months or years) may be necessary. Biodegradable or bioerodible systems are preferred for treatment periods of less than a year. In the future, it might also be possible to use biodegradable or bioerodible systems for treatment periods of 1 year or longer.

In contrast to biodegradable systems, the justification for use of a nondegradable system becomes greater as the required duration becomes longer; generally nondegradable devices offer better control of drug release over longer periods. It also may be easier to produce a more stable formulation in a nondegradable system because some biodegradable systems accelerate the degradation of the incorporated drug.

1.3.7  Type of Drug Delivery System Selected

The choice of biodegradable/bioerodible systems vs. nondegradable systems has been discussed but the nondegradable systems need to be further explored as either nonrefillable or refillable. All of the current intravitreal devices are nonrefillable. But a refillable device might answer the conundrum of how to bring a device to market that is designed to deliver for 20 years with a single surgery; if a fillable

device can be used and refilled once a year or so, it may be useful for the rest of the patient’s life.

Clinical studies of a refillable device might be limited to a year or two, which would make it much more economically feasible than a nonrefillable device. Furthermore, with a refillable device, if a better drug is later approved, that drug may replace the original without further surgery.

The “Achilles heal” of refillable devices is the potential for infection; such a device and its surgical implantation must be designed to protect the port against infiltration of pathogens at all times.

Two often-touted types of drug delivery systems are iontophoretic devices and drug-loaded contact lenses. These devices have significant hurdles to become commercially viable. Iontophoretic devices use a low current to drive drug through biological barriers to the back of the eye, from a topically applied pad. There is little evidence that large molecules can be consistently delivered safely at effective doses. There is, however, some data suggesting that such devices might be proven both safe and effective for small molecules. However, to date, iontophoretic devices have been designed to be used at the practitioner’s office, rather than be self-administered by the patient. Since drugs (ca 300 Da) have a short halflife in the vitreous, to be effective the doses would likely have to be repeated quite frequently. Is the patient going to visit the doctor several times a week for such a treatment? How about once weekly? Would once weekly be effective? Iontophoresis will be discussed more thoroughly in a later chapter. To the back of the eye there are numerous patents and patent applications for drug-loaded contact lenses. Some might even prove to deliver drug to the posterior segment. However, there are many questions left unanswered with such systems. The great bulk of patients with blinding diseases are over age 50. But, less than 5%, in that age range, actually wear contact lenses. How many of these wearers would be willing to give up their brand’s polymer for the drug delivery device polymer? How many noncontact lens wearers would be willing to wear lenses to treat their blinding disease? Will the drug-loaded device affect vision? Will the oxygen permeability of the lens be impaired by the drug and excipients? If impaired, would the cornea be damaged by anoxia? If the drug needs to be delivered in pulses rather than continuous, can a drug-loaded lens deliver in that manner?

Would the contact lens device be daily wear or continuous wear? If daily wear, how would soaking the device in disinfectant affect the device? Would the drug leach into the disinfecting solution during soaking? Would the lens adsorb the disinfectant and become toxic? Alternatively, if the device is continuous wear would protein uptake block the release of the drug or cause ocular irritation?

Would the polymer for the device have a sufficiently low modulus for good fit, yet be sufficiently high to provide strength? Would drug delivery lenses be provided to treat patients with astigmatism or presbyopia? Would the device be available in all diopters and diameters? Would there be devices with several base curves?

Since the combination of all diopters, diameters, and base curves, if provided, would amount to hundreds of different devices, would all these deliver drug at the same rate? If not, how could a clinical trial be conducted with hundreds of potential arms?