Chapter 1

Selection of Drug Delivery Approaches for the Back of the Eye: Opportunities and Unmet Needs

David A. Marsh

Abstract  This chapter provides a strategic overview of drug delivery systems, focusing on practical decisions regarding the choice of a drug delivery formulation or device and, where it may be best administered, in order to safely and effectively reach a targeted lesion. The importance of evaluating risk vs. benefit in all drug delivery system decisions is critically discussed. Additionally, some of the major hurdles, which must be overcome, to bring drug delivery products to market are considered.

1.1  Introduction

Therapies delivered to the back of the eye potentially can treat blinding diseases such as age-related macular degeneration (ARMD), diabetic retinopathy (DR), choroidal melanoma, retinitis pigmentosa, endophthalmitis, Stargardt’s disease, serpiginous choroiditis, branch and central retinal artery and vein occlusions (CRAO and CRVO), glaucoma, and a host of rarer disorders.

Numerous pharmaceuticals and biopharmaceuticals, which have been demonstrated to interact with key receptors involved in ophthalmic disease, have entered the pipelines of pharmaceutical companies. Many of these drugs have been shown to effectively treat an appropriate animal model, which mimic a human ophthalmic lesion. These candidates bring great hope to those with blinding diseases.

However, merely having a good drug candidate is quite different from having a safe, effective product; the drug must be prepared in a nontoxic, stable formulation or device which is optimized for the chosen route of administration. The drug must

D.A. Marsh (*)

Texas Tech University Health Science Center, School of Pharmacy, Abilene, TX, USA e-mail: marshdavida@gmail.com

AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_1, © American Association of Pharmaceutical Scientists, 2011

reach the target receptor in an effective concentration for a sufficient period of time, without eliciting serious adverse effects.

For a variety of reasons, despite researchers best efforts, some of these promising candidates – even if they are delivered to the target tissue at “effective” concentrations for prolonged periods – will not live up to their preclinical expectations. This might be because the human receptor is somewhat different from the animal model receptor: the human has additional or different barriers for the drug to penetrate, the drug is strongly bound to nontarget tissues, the drug is toxic at, or near, the effective concentration, or the human tissue may metabolize or eliminate the drug faster than anticipated from the animal model.

Still other candidates will not be clinically effective because of an inappropriately chosen route of administration, poor stability of the drug or an excipient, inadequate clinical dosing technique, a lack of understanding of the potential for receptor tachyphylaxis, incorrect choice of dosage form and/or dosage level, a mistake in selecting dosing intervals, a failure to understand the influence of the formulation on the physiological barriers between the dosing site and the target tissue, and/or insufficient duration of action to produce significant results.

Multimillion dollar clinical studies of promising drugs have been scuttled as a consequence of one or more of the above factors. It is indeed unfortunate that such clinical failures may have been avoided, if decision-makers had a better appreciation of drug delivery concepts.

This book is dedicated to helping scientists and administration develop such an understanding. Other chapters review the basic principles of drug delivery and describe ophthalmic drug delivery systems such as nondegradable implants, degradable implants, drug suspensions, solutions of macromolecules, hydrogels, microparticles, microneedles, nanosystems, iontophoresis, and fillable devices. Consequently, this chapter will be limited to a strategic overview of various drug delivery systems, focusing on practical decisions regarding the choice of a formulation or device and, where it may be best administered, in order to safely and effectively reach a targeted lesion.

1.2  A Strategic Overview of Drug Delivery Systems

There’s a plethora of literature on drug delivery systems releasing pharmaceuticals to posterior tissues for periods of hours, weeks, months, or years, from various sites of administration within the eye. However, many authors of these publications have not considered risk vs. benefit in their selection of the location of a device or the duration of drug delivery needed to treat a targeted disease. Moreover, few authors have addressed the hurdles, which must be overcome, to bring their system to market. Some blinding diseases require a short-term therapy (e.g., CRVO), while other maladies require intermediateto long-term treatments (e.g. diabetic retinopathy). It is important to note that solubilized drugs have very short vitreal half-lives – usually less than 3 h for a small drug molecule (300 Da). Consequently, a single intravitreal injection of a drug solution may prove to be ineffective, even for use as a short-term therapy.

Intravitreal injections of drug suspensions, gel-forming formulations, microspheres, nanoparticles, and the like are all potential methods of addressing the need for shortterm exposure to drugs. In contrast, many sight-threatening diseases will require long-term, if not lifetime therapy. In these cases, multi-month drug delivery is very important. If a sustained drug delivery formulation can be delivered by intravitreal injection through a 27–30-gauge needle or narrower, that system would likely be safe enough to deliver drug for either short or long duration. However, as a drug delivery system becomes more intrusive into the vitreous – for example, with the use of a 22–25 gauge needle – a target of not less than 3 months of effective and safe drug delivery is needed. And, for any dosage form, which requires vitreal surgery, a minimum of a year – preferably 2 years – of drug delivery should be considered.

If, on the other hand, the sub-Tenon’s route is chosen, the concern about using small gauge needles is considerably lessened because the vitreous is not penetrated; a cannula (Yaacobi et al. 2002) or device (Yaacobi 2002–2006) may be used to deliver a drug for months or years. While less intrusive than the vitreous, it is best to target a formulation to deliver drug for a minimum of 4 weeks, for this procedure. It should be kept in mind that the location of the formulation or device, in this space, may need to be directly over the targeted tissue or the drug may not reach the site of action. Also, if the physician misses the sub-Tenon’s space and accidentally injects into capsule region, the delivery of the drug to the retina and choroid may be significantly diminished.

In addition to thinking about the “minimum” duration of drug delivery system, the researcher should consider the maximum desirable duration; for example, delivery of a neuroprotectant, for prevention of the blinding effects of glaucoma, may require a life-long treatment. While it is feasible to design a nondegradable device to deliver a highly potent very stable drug for 20–30 years without refill, the researcher needs to question whether decades of drug delivery would be a good target to pursue. Typically, the duration of drug delivery will be proportional to the number of years required to complete a clinical trial and to the cost of bringing the product to market. Regulatory agencies may require the clinical study to continue until the last device implanted is devoid of drug. It is even conceivable that a regulatory agency would require that the patients be monitored for the rest of their lives in order to assure that the emptied device causes no problems.

Clearly, the cost of a 20-year clinical study, prior to approval, would be prohibitive to pharmaceutical companies. Furthermore, even the most stable drugs tend to degrade with time. How would a researcher demonstrate to a regulatory agency that the drug will be stable for decades in an in vivo environment? How would the researcher demonstrate that a drug degradation product or metabolite would not cause a problem after several years of exposure to the eye? These are not trivial questions. Preclinical studies lasting 20 years in order to justify that a system is sufficiently safe and stable to warrant a 20-year clinical study is daunting, to say the least.

A further concern, which the researcher must take into account, is that the biopharmaceutical and pharmaceutical pipelines of new drugs are rapidly expanding. What happens if a competitor gains approval of a superior drug while the 20-year clinical study is in its second year? Would a company be likely to continue that expensive