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Contributors
https://t.me/med1917
Thomas W. Gardner, PhD Department of Ophthalmology,
Cellular and Molecular Physiology, Penn State College of Medicine,
Hershey, PA, USA
Dayle H. Geroski, PhD Emory University School of Medicine, Eye Center,
Atlanta, GA, USA
Brian C. Gilger, DVM MS Dipl. ACVO, Dipl. ABT Department of Ophthalmology,
College of Veterinary Medicine, North Carolina State University, Raleigh,
NC, USA
Rocío Herrero-Vanrell, PhD
Department of Pharmacy and Pharmaceutical
Technology, School of Pharmacy, Complutense University, Madrid, Spain
Ken-ichi Hosoya, PhD Department of Pharmaceutics, Graduate School
of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Patrick Hughes, PhD Allergan, Inc., Irvine, CA, USA
Cristina Kendall, MS Department of Ophthalmology, Emory University
School of Medicine, Atlanta, GA, USA
Esther S. Kim, BS Department of Ophthalmology, Emory University
School of Medicine, Atlanta, GA, USA
Uday B. Kompella, PhD Nanomedicine and Drug Delivery Laboratory
Department of Pharmaceutical Sciences, University of Colorado,
Aurora, CO, USA
Department of Ophthalmology, University of Colorado,
Aurora, CO, USA
Ashutosh A. Kulkarni, PhD Department of Pharmacokinetics,
and Drug Disposition, Allergan Inc., Irvine, CA, USA
Dennis Lee, PhD
Ophthiris, GlaxoSmithKline Pharmaceuticals,
King of Prussia, PA, USA
Susan S. Lee, MS Allergan, Inc., Irvine, CA, USA
Allia K. Lindsay, BS Department of Ophthalmology, Emory University
School of Medicine, Atlanta, GA, USA
Tao L. Lowe, PhD Department of Pharmaceutical Sciences, School of Pharmacy,
Thomas Jefferson University, Philadelphia, PA, USA
Department of Pharmaceutical Sciences, College of Pharmacy
University of Tennessee Health Science Center, Memphis, TN, USA
Jenifer Mains, M.Pharm Strathclyde Institute of Pharmaceutical
and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK
David A. Marsh, PhD Texas Tech University Health Science Center,
School of Pharmacy, Abilene, TX, USA
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Contributors
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Bernard E. McCarey, PhD Emory University School of Medicine, Eye Center,
Atlanta, GA, USA
Peter Milne, PhD Bascom Palmer Eye Institute, University of Miami Miller
School of Medicine, Miami, FL, USA
Gauri P. Misra, PhD Department of Pharmaceutical Sciences,
Thomas Jefferson University, School of Pharmacy, Philadelphia, PA, USA
Ashim K. Mitra, PhD
Division of Pharmaceutical Sciences,
University of Missouri-Kansas City, School of Pharmacy, Kansas City, MO, USA
Ross J. Molinaro, PhD Department of Pathology and Laboratory Medicine,
Emory University School of Medicine, Atlanta, GA, USA
Sheree S. Mosley, BS Department of Ophthalmology, Emory University
School of Medicine, Atlanta, GA, USA
John M. Nickerson, PhD Department of Ophthalmology, Emory University,
Atlanta, GA, USA
Timothy W. Olsen, MD Department of Ophthalmology, Emory Eye Center,
Emory University School of Medicine, Atlanta, GA, USA
Machelle T. Pardue, PhD Department of Ophthalmology and Rehabilitation
Research and Development Center of Excellence, Atlanta VA Medical Center,
Emory University School of Medicine, Atlanta, GA, USA
Jean-Marie Parel, PhD Bascom Palmer Eye Institute,
University of Miami Miller School of Medicine, Miami, FL, USA
Samirkumar R. Patel, PhD School of Chemical and Biomolecular Engineering,
Georgia Institute of Technology, Atlanta, GA, USA
Indu Persaud, MS
Department of Pharmaceutical Sciences,
University of Colorado, Aurora, CO, USA
Mark R. Prausnitz, PhD School of Chemical and Biomolecular Engineering,
Georgia Institute of Technology, Atlanta, GA, USA
Michael R. Robinson, MD Allergan, Inc., Irvine, CA, USA
Aron D. Ross, PhD Triton Biomedical, Inc., Laguna Beach, CA, USA
Robert I. Scheinman, PhD Department of Pharmaceutical Sciences,
University of Colorado, Aurora, CO, USA
Masanori Tachikawa, PhD Department of Pharmaceutics,
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama,
Toyama, Japan
Lay Ean Tan, PhD Strathclyde Institute of Pharmaceutical and Biomedical Sciences,
University of Strathclyde, Glasgow, Scotland, UK
xii Contributors
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Puneet Tyagi, M.Pharm Nanomedicine and Drug Delivery Laboratory,
University of Colorado, Aurora, CO, USA
Ravi D. Vaishya, B.Pharm Division of Pharmaceutical Sciences,
University of Missouri-Kansas City, School of Pharmacy, Kansas City, MO, USA
Sunil K. Vooturi, PhD Nanomedicine and Drug Delivery Laboratory,
University of Colorado, Aurora, CO, USA
Alan L. Weiner, PhD
Clive G. Wilson, PhD Strathclyde Institute of Pharmaceutical
and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK
Alison C. Ziesel, BS Department of Ophthalmology, Emory University
School of Medicine, Atlanta, GA, USA
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
DrugDel Consulting, LLC, Arlington, TX, USA
Chapter 1
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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, ser-
piginous 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
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye,
AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_1,
© American Association of Pharmaceutical Scientists, 2011
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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 intermediate- to 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.
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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
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study for the remaining 18 years, while the competitor is eating its lunch? So, designing
a nonrefillable device to deliver a drug for decades may not be a good decision.
Still, when delivering a neuroprotectant, wouldn’t it be in the best interest of the
patient to have a single surgically implanted device delivering for the rest of his
life? Is there an innovative regulatory approach to help patients benefit from such a
device? Would the FDA consider an NDA filing and possible approval after only
2 years of a 20-year study, if there is a commitment to complete the remaining study
and to maintain and update contact information for all postapproval patients? Perhaps.
And, if granted approval after 2 years, would the sales of the device support the
expense of the clinical study and the labor of maintaining the patient database? Could
a competitor knock this very long-duration product off the market with a more effective shorter-acting system? Could an unanticipated adverse effect force a product
recall and a class-action lawsuit? Is there any way this could be a profitable venture?
Undoubtedly, a 20-year clinical study is an extreme example of decision-making.
But, the point is that the researcher must consider a trade-off between what best
benefits the patient and what is practical; while shortening the duration of a drug
delivery system may seem like “planned obsolescence,” the patient will not benefit
at all, if the device is designed to be too expensive to gain regulatory approval or it
takes too long for the sale of the device to recover its investment. Clearly, life-long
treatment with a single surgery is a desirable target, but perhaps only a refillable
device will meet the need.
1.3 Specific Approaches to Drug Delivery
for the Posterior Segment
Decisions affecting the design of a system to deliver a given drug to the target tissue
should take into consideration several factors: the influence of physicochemical
properties on drug delivery and pharmacokinetics (PKs) (1.3.1), chosen route of
administration (1.3.2), location of the target tissue (1.3.3), potency of the drug
(1.3.4), need for continuous or pulsatile delivery (1.3.5), duration of drug delivery
necessary to induce and maintain efficacy (1.3.6), type of drug delivery system
selected (1.3.7), PK properties of the drug (1.3.8), local and systemic toxicity of the
drug and its metabolites (1.3.9), previous use of excipients in the eye (1.3.10), and
development and strategic teams’ input (1.3.11).
1.3.1 The Influence of Physicochemical Properties on Drug
Delivery and Pharmacokinetics
PKs will be discussed in great detail in a later chapter. This section, therefore, will
focus only on the influence of a drug’s physicochemical properties as it relates to
creating a drug delivery system. Physicochemical properties such as water solubility,
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partition coefficient, PKa, ion pairing, particle size, drug stability, molecular size,
and polymorphic forms are very important characteristics, which govern a drug’s
ability to reach the targeted receptor. Consequently, it is helpful to understand these
parameters in order to develop a stable drug delivery vehicle and to select the optimal
site of administration.
A drug that is highly water soluble will be difficult to deliver in a controlled
dosage manner. Moreover, highly water soluble drugs will generally have low permeability through lipophilic tissue and, consequently, would be unlikely to penetrate
target tissues such as the retina and choroid in effective concentration. Typically,
water-soluble drugs are rapidly eliminated and have short half-lives.
On the other hand, highly lipophilic drugs are difficult to dissolve in the aqueous biological environment. A poorly water-soluble drug typically will have low
tissue permeability because diffusion is dependent upon the concentration of drug
in solution. Formulations which include a pharmaceutical aid for the dissolution of
such a drug (surfactants, cyclodextrins, etc.) may increase tissue concentration but
would decrease duration of delivery. Moreover, unless the solubility-enhancing
excipients travel with the drug into the tissue, the drug may precipitate within cells
and may disrupt vital functions. And, even if the drug and solubilizing excipients
are injected directly into the tissue (e.g., vitreous), the excipients may be diluted and
the drug will then likely precipitate; in this case, the excipients would be eliminated much faster than the drug.
On the positive side of highly lipophilic drugs, an intravitreal injection of a
suspension – or a formulation which precipitates in
vivo – may create a reservoir
for prolonged release of a drug; for example, triamcinolone acetonide suspension
injected into the vitreous may deliver an effective dose of the steroid for months.
However, it should be noted that, just because drug particles settle in the vitreous,
does not necessarily mean that the drug will be available to reach its target; the
drug may be unavailable to targets for a number of reasons such as endocytosis by
nontarget tissue(s), low solubility, drug degradation, or metabolism.
While it is more likely that an extremely lipophilic drug would be effective than
a highly water soluble drug, it is best to consider that both species will be difficult
to formulate. If a promising drug is at either of these solubility extremes, it may be
wise to evaluate a prodrug approach, in parallel, or instead, of devoting enormous
resources in an effort to develop a viable formulation.
At least equally important as a drug’s solubility, the drug’s partition coefficient
plays a vital role in passive diffusion; the hydrophobic/hydrophilic balance of drug
molecules usually determines the degree in which a pharmaceutical will be taken up
by tissues. A drug solution injected into the vitreous will diffuse in a concentration
dependent manner (assuming that the drug remains in solution). In most cases,
flow and ocular pressure will be only minor contributors to vitreal drug distribution;
an intravitreal injection of a solution at the pars plana will distribute in declining
gradients throughout the vitreous to reach the macular at roughly 1/10th the
concentration of the injected formulation (Missel 2002).
From its local concentration in the vitreous, a drug diffuses into the retina
depending on a number of factors, which include the drug’s concentration in solution,
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its ability to partition between tissues, its bioelimination rate, and the drug’s stability.
From the retinal tissue, the drug will travel to the choroid and then to the sclera.
It should be kept in mind that the Bruch’s membrane is between the retina and
choroid and can serve as a barrier to drugs. However, in ARMD, this barrier is
typically disrupted by choroidal vessels, which modify the architecture of the retina.
Consequently, drugs may more readily permeate the choroid after an intravitreal
administration to a patient with macular degeneration.
Drugs may be delivered to the choroid and retina from a subTenons site of
administration. The sclera appears to be rather “porous” to drugs. Assuming the
drug is sufficiently liposoluble, it will also penetrate the choroidal tissue and then
enter the retina. The Bruch’s membrane may serve as a barrier between the choroid
and the retina but, again, in ARMD this may be disrupted. Some drug will be eliminated by the choroidal blood vessels.
It is likely that the partition coefficient also plays an important role in a drug
migrating posteriorly after topical ocular administration (Tamilvanan et
al. 2006).
Very few drugs reach the back of the eye in effective concentration by this path
because there is substantial dilution of a drug by tear fluid, followed by precorneal
drainage. Also, there are numerous physiological barriers which block the drug
from reaching posterior tissue (Short 2008).
One possible route around these barriers may be by trans-limbal/intrascleral
migration (Ottiger et al. 2009). A topical formulation for treating a blinding disease would be a very important discovery because it would be both noninvasive
and patient friendly.
PKa is another important factor in drug permeation of lipophilic tissue (e.g.,
retina and choroid); generally, drugs, which are unionized at physiological pH, have
a better opportunity to reach the target tissue than ionized drugs; however, there
may be exceptions to this rule (Brechue and Maren 1993). Also, ion-pairing may
assist ionized drugs to penetrate tissue by decreasing the overall charge.
Particle size also may play an important role in drug distribution. Formulations
with smaller particle size have a greater net surface area than identical formulations
with larger particle size. Generally, because of the higher surface area, the drug divided
in smaller particles will dissolve at a faster rate than if the drug was in larger particles.
Therefore, small-particle formulations would normally be expected to deliver a higher
solubilized concentration of drug in vivo, in a shorter period of time.
Formulations with smaller drug particles might stay suspended in the vitreous
longer than larger ones; this would give the drug an opportunity to spread more
evenly and to more readily penetrate the retina either by localized dissolution followed by diffusion or by endocytosis. However, if the particles remain suspended
in the vitreous too long or settle on the retina in large concentration, they may impair
vision and cause temporary blindness for days or weeks. Alternatively, if a formulation with small particles settle and unite to form a mass in the vitreous, the formulation
may have nearly identical properties as one with larger particles. Similarly, large
particle suspensions injected into the sub-Tenon’s space might be expected to
have a longer duration than smaller particles of the same drug. But, here too,
the smaller particles might form a mass and behave much like the larger particles.
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Or, macrophages might carry away the smaller particles, while ignoring the larger
ones, resulting in a higher concentration of drug in the target tissues and longer
duration with latter formulation. In contrast, drugs, which inhibit macrophage
digestion, may produce the opposite results.
Drug molecule size is another physicochemical property that can play a role in
tissue distribution. In the vitreous, molecules with a higher molecular weight (e.g.,
oligonucleotides, polypeptides, proteins) generally have a longer half-life than
smaller drug molecules. However, lipophilicity, dose, and solubility also play important roles in vitreal half-life of a drug (Dias and Mitra
2000; Durairaj et al. 2009).
Molecules, both small and large (285–69,000 Da) readily diffuse through the sclera
(Maurice and Polgar 1977; Geroski et al. 2001). In contrast, the retinal pigment
endothelium (RPE)-choroid barrier is about 10–100 times less permeable to large
molecules than the sclera (Pitkänen et al. 2005).
Polymorphism is another physicochemical property which can be important to
drug delivery. Polymorphs may differ in filterability, solubility, dissolution rate,
chemical and physical stability, melting point, color, refractive index, enthalpy,
density, viscosity, bioavailability, and many other properties (Llinàs et al. 2007).
The importance of understanding the polymorphic forms of a drug and their
stability cannot be understated. In 1998 – 2 years after launch – Abbott Labs discovered that several lots of Ritonavir capsules failed the QC dissolution testing.
Microscopy and X-ray powder diffraction indicated that a new polymorph had
formed and that the new material was more thermodynamically stable and had
greatly reduced solubility compared to the original crystal form (Bauer et al. 2001).
Abbott lost hundreds of millions of dollars in the expense of a major recall, in lost
revenues, and in R&D efforts to reintroduce the drug. But this change was more
than just a costly and embarrassing problem; some AIDS patients may have been
given the nondissolving dosage form, while others, due to the recall, were deprived
of this life-extending therapy altogether.
Polymorphism is a potential problem with all types of dosage forms, including
ophthalmic formulations and drug delivery systems. For example, after completing
a phase I/II clinical study of an intravitreal suspension of a steroid, an ophthalmic
drug company belatedly discovered that there were three polymorphs of the drug in
the raw material: the mix was 80% “alpha”, 15% “beta,” and 5% “gamma” polymorphs. Immediately critical questions arose: Would future raw material lots always
contain the same ratio of polymorphic forms? Did the ratio between the polymorphic forms change during manufacture, storage, and/or distribution? If the ratio of
polymorphs changes under any of these conditions, would the formulation’s efficacy, stability, and safety observations be reproducible in the future?
These are some of the questions that regulatory authorities would ask, with the
highly likely outcome that the information generated in the clinical study would be
deemed worthless, causing the loss of time to market and millions of dollars.
Fortunately, in this particular case, further investigation showed that the suspension’s processing steps had converted the beta and gamma crystal forms in the raw
material to the alpha polymorph. The final clinical suspension was composed of
100% of the alpha form; it also was quite fortuitous that the formulation remained
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