in the alpha crystal form throughout the entire clinical study. The company got a lucky break….pure and simple.

Potential polymorphic changes in both drugs and excipients need to be studied and understood early in a research program and then monitored for changes throughout development. It should be kept in mind that, once elevated to the development phase, the expectation will be that a product will be moved rapidly to clinical studies and to market. Consequently, if polymorphism is overlooked in the research phase, the mistake may not be caught during the rush to market; the formulator should include a “check for polymorphs” in the stability study regimen.

1.3.2  The Chosen Route of Administration

Drugs have been delivered to the back of the eye by the oral, transdermal, topical ocular, intravitreal, intraarterial, sub-Tenon’s, retrobulbar, suprachoroidal, intrascleral, transscleral, and subconjunctival routes of administration (Tzekov et al. 2009). Some of these routes will be discussed in other chapters; this section will focus on the advantages and disadvantages of each route of administration, provide examples of drug delivery systems for each route, and highlight the tissues where drug delivery formulations and devices would be most effective.

The oral route is advantageous in that it is easy for the patient to self-administer, facilitating good compliance for daily dosing. This route is also relatively inexpensive because the cost of manufacturing an oral dosage form is low and because medical intervention or supervision is relatively minor.

On the other hand, systemic exposure to the active drug and metabolites increases the possibility for serious adverse effects. Moreover, systemic dilution and difficulty in drug penetration of the blood-retinal barrier may result in a relatively low concentration at the active site with potentially little or no efficacy. Also, with oral dosing, the “first-pass effect” in the liver may substantially metabolize the active. Drugs taken by mouth may result in considerable patient-to-patient variability in drug blood levels, side effects, and efficacy. Furthermore, a drug’s concentration in the blood is subject to significant peaks and valleys, which might range between toxic and subeffective levels.

Notwithstanding these hurdles, oral dosage forms have been administered to treat – or attempt to treat – back of the eye diseases. For example, a clinical study by the National Eye Institute (ARED Research Group 2001a, b) has demonstrated that certain orally administered vitamins and minerals retard the progression of ARMD. Both zinc and antioxidants significantly­ reduced the odds of developing advanced ARMD in a high-risk group (e.g., Ocuvite®, ICAPS®).

There are several other examples of oral therapies for the eye. Aspirin tablets (250–500 mg) appear to be more beneficial in the treatment of CRAO than intravenously administered heparin (Arnold et al. 2005). Oral administration of steroids has been one approach to treating noninfectious uveitis. A new oral therapy, Luveniq,™ (voclosporin), an immunosuppressive agent, is claimed to have demonstrated

“clinically meaningful efficacy and enabled preservation of vision in treated patients” in uveitis patients (Lux 2010). Assuming this drug is approved by regulatory agencies, it may not only replace oral steroid for this use but also possibly ocular injections, implants, and topical drops.

Oral dosing of memantine, a neuroprotectant, has been shown to enhance the survival of retinal ganglion cells in the inferior retina in primates (Hare et al. 2004a, b). However, in a phase III clinical study evaluating its benefit in glaucoma­ patients, memantine did not demonstrate efficacy different from a placebo­ (Osborne 2009). Moreover, a relatively high incidence of adverse effects, such as dizziness,­ headache, constipation, and confusion, are associated with oral dosing of this drug. Likewise, a clinical safety study evaluating oral eliprodil as an ocular neuroprotectant, demonstrated significant patient-to-patient variation in blood levels­ of the active; when one patient, having a particularly high blood concentration of drug, experienced a lifethreatening prolongation of the QTc interval, the study was discontinued.

Although the transdermal route has not been used in man for treating posterior ophthalmic diseases, it is a promising alternative to oral dosing; for example, a transdermal patch of eliprodil, studied in minipigs, demonstrated zero order drug delivery at purported effective drug levels; this route would likely minimize the patient-to-patient variation in blood levels and toxicity, which was observed in the oral-dosing clinical.

Similar to the transdermal route of administration, intravenous dosing avoids the “first-pass effect” while providing a very consistent, usually well-controlled, blood level of drug. This route is currently the path of choice for photodynamic therapy. In ARMD, blood vessels behind the retina grow under and within the macula and leak blood and fluid. A bolus intravenous infusion of a light-activated drug formulation allows the photosensitive pharmaceutical to seep into the tissue adjacent to the leaky vessels. Shortly after initiating the infusion, a low-intensity laser beam is focused through the cornea to posterior tissue, photoactivating the drug, which then destroys the defective sight-impairing vessels. This is a marginally effective therapy.

The intravenous route also may be a good choice for treating CRAO. Since the flow of the blood in the central retinal artery is toward the eye, topical ocular, intravitreal, sub-Tenon’s, suprachoroidal, intrascleral, retrobulbar, and subconjunctival routes of administration are unlikely to deliver an effective concentration of drug to the site of blockage.

The intravitreal and sub-Tenon’s routes are currently targets for human implantation of drug delivery formulations and devices and are the most promising ways to deliver drugs at effective and safe concentrations to the back of the eye. Drug delivery devices have been explored in the intrascelaral, transscleral, subconjunctival, and suprachoroidal spaces in animals but, to date, no advantage has been demonstrated over intravitreal or sub-Tenon’s administration.

Intravitreal administration of a drug delivers it proximate to the site(s) of action, where there are few physiological barriers to overcome. Suspensions may form a depot for prolonged delivery. Both biodegradable and degradable drug delivery devices can provide a continuous dose of a drug for months or years. An important advantage of this route is that systemic exposure to the drug is limited

and, consequently, systemic adverse effects minimized. However, this route of administration comes with some risks. Common adverse effects include: conjunctival hemorrhage, eye pain, vitreous floaters, retinal hemorrhage, vitreous detachment, and intraocular inflammation.

Endophthalmitis, retinal detachment, and traumatic cataract occur in proportion to the number of times the vitreous is breached; although the incidence of these adverse effects is low, the chance of occurrence is additive. Fear of this procedure may cause some patients to avoid therapy.

More than any other method of administration targeting posterior diseases, the intravitreal route predominates because the injection/implantation is relatively straightforward and the chance of successful delivery to the target is facilitated by the drug being delivered near target tissues. Commercial intravitreal pharmaceuticals, for treating posterior diseases, include Ozurdex,™ Vitrasert,® Retisert,® Lucentis,® Triesence,™ Posurdex,® Macugen,® and Trivaris.™ In addition, numerous formulations and drug delivery devices have been patented, some currently in preclinical and clinical studies. The potential for adverse effects caused by penetrating into the vitreous makes long-acting products highly desirable because the number of intrusions would be minimized.

It is important to note that, just because the drug is placed in the vitreous, does not guarantee that the drug will reach the target tissue in a safe, effective dose because many factors affect a drug’s permeation into the tissue. Intravitreal formulations and devices will be discussed in greater detail in several upcoming chapters.

The sub-Tenon’s space – which is above the outer surface of the sclera and below the Tenon’s capsule – is an excellent location to administer drug formulations and devices for the treatment of posterior ocular diseases; it is less invasive than the intravitreal route and, with training, fairly easy and rapid to access. Using this route of administration, the drug can be delivered near its site of action, where it is likely to permeate the sclera and reach the choroid and retina. From this juxtascleral space, there are three barriers which the drug must permeate in order to reach the neuroretina: the sclera, Bruch’s membrane-choroid, and RPE (Kim et al. 2007a, b). The sclera is quite permeable; there is evidence that even large molecules (e.g., polypeptides and proteins) may diffuse through this tissue (Olsen et al. 1995). The Bruch’s membrane may be disrupted in ARMD and DR, and therefore drugs may not encounter an intact barrier (Chong et al. 2005; Peddada et al. 2002; Ljubimov et al. 1996). In order to penetrate the RPE in effective concentrations, the drug will generally need to be in substantial concentration, be unionized, and fairly hydrophobic. These conditions are no different than a drug administered in the vitreous. Yet, sub-Tenon’s administration avoids penetrating the vitreous and therefore is a safer alternative.

This route, while promising, has its pitfalls. In rabbits, anecortave acetate readily penetrates intact tissue barriers to provide a purported effective concentration in the tissue; however, the drug only moves laterally in the choroid and retina about 1–2 mm; this may be due to this drug’s hydrophobic nature or perhaps some other property unique to anecortave acetate. The point is that this observation suggests that a drug, or drug delivery device, ideally should be placed, in the sub-Tenon’s space, directly over the macula, for treatment of ARMD, while the same drug may

need to be spread throughout the episcleral space, as much as possible, in order to treat DR. Of course, other drugs with different physicochemical properties may afford better distribution characteristics.

Another potential problem occurs when an injection of drug suspension or solution is administered into the tight sub-Tenon’s space; a large portion of the dose may reflux due to backpressure. This can be prevented by first expanding the space with a probe prior to administration of the formulation. Alternatively, a counterpressure device may prevent or minimize reflux (Kiehlbauch et al. 2008).

An additional common pitfall is that the practitioner may accidently inject into the Tenon’s capsule, rather than into the space below it; this error would cause the bulk of the drug to eliminate rather than reach the target tissue. It should also be noted that there is an increased risk of scleral perforation in myoptic patients (Canavan et al. 2003).

Even with all these potential complications, the sub-Tenon’s space is still a viable spot to place drug delivery formulations and devices. For example, in rabbits, juxtascleral devices were surgically implanted directly over the macula and were demonstrated to produce a sustained near-zero order delivery of anecortave acetate at targeted concentrations for a period of 2 years (Yaacobi et al. 2003). When the study was terminated, 40% of the drug remained in the devices, suggesting that the device might have continued delivering the steroid for a substantially longer period. Similar devices have been designed specifically for human use (Yaacobi 2002–2006); these have been evaluated in a phase I safety study and were successfully implanted over the human macula.

Although many practitioners prefer retrobulbar administration of local anesthetics, sub-Tenon’s administration may be a safer site because the former route allows much of the drug to be quickly eliminated systemically, where the spike in systemic drug concentration may cause serious adverse effects (Buys and Trope 1993; Tokuda et al. 2000). Retrobulbar administration is not a likely route for long-term delivery of drugs for treatment of posterior diseases except, perhaps, for delivering a neuroprotectant to the optic nerve (Zhong et al. 2008).

Studies in rabbits and horses suggest that administration of drug formulations and devices into the intrascleral space is a feasible location for delivery of drugs to the posterior segment of the eye (Einmahl et al. 2002; Okabe et al. 2003; Kim et al. 2007a, b). For example, a betamethasone nondegradable implant has been demonstrated­ to yield zero order release for a period of 4 weeks in rabbits at or above anti-inflammatory effective concentration. However, while a drug delivery system may be placed closer to the site of action by this route, there is no evidence that it would deliver drug more effectively than from the sub-Tenon’s route. Indeed, the sclera is quite permeable to drugs, so the advantage of placing a device closer to choroid may be insignificant, while the surgery to create a pocket in the sclera is somewhat more complicated than in the sub-Tenon’s space.

As a site for drug delivery to posterior tissue, the subconjunctival route has produced mixed results in animal studies (Kompella et al. 2003; Amrite and Kompella 2005; Cardillo et al. 2010). The suprachoroidal space appears to be superior to the subconjunctival route in serving as a reservoir for sustained-release pharmaceuticals