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4 Systemic Route for Retinal Drug Delivery: Role of the Blood-Retinal Barrier
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Tomi M, Terayama T, Isobe T et al (2007b) Function and regulation of taurine transport at the inner
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Umapathy NS, Gnana-Prakasam JP, Martin PM et al (2007) Cloning and functional characteriza-
tion of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types. Invest Ophthalmol Vis Sci 48:5299–5305
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Chapter 5
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Topical Drug Delivery to the Back of the Eye
Thomas Gadek and Dennis Lee
Abstract A topical eye drop represents the least invasive method for targeting drugs
to the back of the eye. Systemic exposure and potential toxicity are minimized
relative to oral drugs, and an eye drop offers a more patient-friendly experience
compared to intravitreal or periocular injections. Ocular tissue barriers and clearance
mechanisms render this mode of delivery relatively inefficient for most drugs, and
eye drop delivery for posterior indications pose a challenging proposition. However,
there are presently a number of examples of compounds in clinical development for
posterior diseases of the eye. This chapter will detail our mechanistic understanding
of how these drugs transit to the back of the eye.
5.1 Introduction
Earlier chapters have described the distribution of drugs to the posterior tissues
from intraocular injections and sustained release formulations using intravitreal,
periocular, or episcleral strategies. We will now focus on the promises and challenges associated with the development of an ophthalmic eye drop formulation for
the treatment of diseases in the back of the eye. A topical eye drop represents the
least invasive method for targeting drugs to the back of the eye. However, this preferred and well-established delivery method shares all of the challenges of drug
distribution, metabolism, and clearance with the other delivery strategies, and has to
overcome the additional hurdle of inefficient drug penetration beyond the cornea/
conjunctiva barrier after topical delivery.
In contrast to just a decade ago, there is now a developing body of data supporting
the delivery of therapeutic concentrations of drug to the back of the eye via topical
T. Gadek (*)
OphthaMystic Consulting, Oakland, CA, USA
e-mail: gadek@pacbell.net
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_5,
© American Association of Pharmaceutical Scientists, 2011
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dosing regimens (Geroski and Edelhauser 2000). Drugs may reach the posterior
tissues via local absorption and diffusion in the ocular tissue of the dosed eye,
absorption into systemic vasculature, and circulation to the posterior of the dosed
and un-dosed fellow eye, or a combination of the two. Ultimately, what is most
important for therapy is whether efficacious drug levels are attained and sustained
at the posterior site of action. However, the route by which it accesses the back of
the eye could significantly impact the developability of a drug. Local delivery and
transit would be expected to require a lower dose for therapeutic benefit, and hence
minimize the potential for systemic toxicity.
Limitations to the successful delivery of a drug via topical eye drops include the
drug’s distribution across the surface of the eye in tear and periocular fluids, the
clearance of drug from tear fluid by blinking and subsequent nasolachrymal drainage
(Goodman and Gilman 2005; Reed 2008), the barrier to penetration presented by
corneal and conjunctival epithelia (Chung et al. 1998), efflux of the drug by the corneal
and conjunctival epithelia (Zhang et al. 2008; Mannermaa et al. 2006), metabolism
in ocular tissues and clearance from ocular compartments including the aqueous,
vitreous, retina, and choroid through the combined intraocular vascular and lymphatic flows sweeping drug from ocular tissue into the systemic circulation (Ghate
et al. 2007). However, recent advances in the understanding of the barriers to ocular
absorption and their differences across the physiologic topography of the eye have
defined three routes of drug penetration from the cornea/conjunctiva surface to the
retina (Mizuno et al. 2009) (see Fig. 5.1): (1) the trans-vitreous trans-corneal diffusion followed by entry into vitreous and subsequent distribution to ocular tissues, (2)
the periocular route – permeation through the conjunctiva to access the periocular
fluid of the tenon, diffusion around the sclera followed by diffusion across the sclera,
choroid, and retina, and (3) the uvea-scleral route – trans-corneal diffusion, passage
through the anterior chamber, and drainage via the aqueous humor to the uvea-scleral
tissue towards the posterior tissues (Ahmed and Patton 1985; Tojo 1988; Geroski and
Edelhauser 2001; Acheampong et al. 2002; Mizuno et al. 2009). Recent studies of
the dynamics of intraocular drug distribution (Durairaj et al. 2009, chapters in this
book) have made it clear that once drug penetrates the outer surfaces of the eye, the
delivery of topical drugs for the treatment of diseases in the posterior segment is a
more achievable goal. The reader should be cognizant that in the real world where
drugs have been reported to reach the retina via topical drops, that the data often does
not allow one to identify a single local transit route. Rather, interpretation of data
usually leaves open the possibility, or even strongly suggests that drug reaches the
posterior segment of the eye by a combination of the routes described above, and in
some cases includes a systemic component.
There are a number of publications documenting the distribution of eye drops to
posterior tissues as measured by animal pharmacokinetics (PK) and/or efficacy
studies, but until recently, few of them provided the supporting data required to
delineate the transit route of the drug. Measurement of systemic drug levels and the
ability of systemic drug to reach posterior tissues of the eye (as measured by PK or
efficacy), comparison of efficacy or drug levels between dosed and nondosed eyes,
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Fig. 5.1 Three potential routes for penetration of topically applied ophthalmic drugs to the posterior
segment. (1) The trans-vitreous route: trans-corneal diffusion followed by entry into vitreous and
subsequent distribution to ocular tissues (blue arrow). (2) Periocular route: diffusion around the sclera
followed by trans-scleral absorption (red arrows). (3) Uvea-scleral route: trans-corneal diffusion
followed by progression through the uvea-sclera (green arrow). Adapted from Mizuno et al. (2009)
and evaluating relative drug concentrations in ocular tissues are all methods for
gaining insight into the transit route of drugs. The following section will highlight
examples of the local transit routes previously described, and which have been characterized via a combination of the above techniques for a number of small molecules
and proteins. In the subsequent section, case studies detailing agents with potential
therapeutic benefit in the clinical setting will be presented.
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5.2 Drug Distribution
5.2.1 Drug Distribution from the Anterior Ocular Surface
to the Posterior Segment
In comparison to studies of the oral bioavailability of drugs and their absorption
across intestinal tissue, the penetration of drugs into the eye from drops applied to
anterior ocular surface appears to be driven by a drug concentration gradient established at the corneal and/or scleral surfaces and is less dependent on the number of
potential hydrogen bonds, molecular weight, or lipophilicity of the drug (Ahmed
et al. 1987; Lipinski et al. 2001). At the corneal epithelial surface, drug can cross
the epithelium either by going between (para-cellular) or through (trans-cellular)
the epithelial cells. Drug penetration by either of these routes is linearly related to
drug concentration in tear and favors drugs formulated at high concentrations and
with long residence times on the ocular surface (Table 5.1) (Huang et al. 1983;
Chung et al. 1998; Pade and Stavchansky 1997). In general, hydrophilic drugs
cross the corneal epithelial barrier by the para-cellular route (e.g., Inulin or
Atenolol); they are restricted to the aqueous extracellular environment and must
move through the limited space in the tight junctions between epithelial cells. In
contrast, lipophilic or hydrophobic drugs cross the corneal epithelial barrier by the
trans-cellular route (e.g., Timolol or Propanolol), have the advantage of a much
larger surface area or window of absorption, and generally have a higher permeability across the epithelium.
In marketed drugs, excipients can be added to the formulation to enhance the
drugs’ penetration into ocular tissues. For example, the addition of EDTA to the
Atenolol formulation loosens the tight junctions between epithelial cells by chelating
the calcium needed to maintain their integrity (Rojanasakul and Robinson 1991), and
increases the para-cellular space and penetration of Atenolol through the corneal
epithelium by the para-cellular route (Chung et
trans-cellular uptake of Propanolol with the addition of EDTA to the formulation.
Once in the corneal stroma, there is typically little resistance at the corneal
endothelium to diffusion further into the anterior chamber (Huang et al. 1983). In
studies of Inulin vs. Timolol (Ahmed and Patton 1985) and Propranolol vs. Atenolol
(Chung et al. 1998) in rabbits after application of an ophthalmic drop, drug levels
were highest in the cornea with sequentially declining levels in the sclera, aqueous
humor, and vitreous humor. Interestingly, levels in the posterior sclera are within a
fewfold of those in the cornea for Inulin and Timolol in as little as 20 min after a
drop is applied to the cornea surface. Consequently, it appears that once on the surface of the eye, there can be rapid distribution of drug driven by a concentration
gradient across the compartments of the eye.
To distinguish transit via the periocular trans-scleral route from the trans-vitreous
and uvea-scleral trans-corneal routes, Patton devised a chamber which could be placed
with a tight seal to the ocular surface around the cornea (Ahmed and Patton 1985).
Drug introduced into the chamber is restricted to contacting the corneal surface only.
al. 1998). No effect is seen on the
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Table 5.1 The concentration of inulin, timolol, propanolol, and atenolol 20 min after administration
of a drop to a rabbit eye
Permeability
vitro
in
6
(10
cm/s)(+Cornea) (−Cornea)
Inulin (0.65%)
(hydrophilic,
MW 5,000)
Paracellular vs.
Drug levels in
vivo (mg/g)
trans-cellular
% F po
uptake
0 Paracellular Cornea 22.80 1.87 Cornea 0.55
Sclera 7.82 8.45
AH 2.10 0.03 Sclera 2.54
VH 0.03 0.02
Timolol (0.65%)
(lipophilic,
MW 316)
60 Transcellular Cornea 84.5 2.61 Cornea 7.98
Sclera 9.5 10.7
AH 7.9 0.03 Sclera 40.8
VH 0.08 0.03
(−EDTA) (+EDTA)
a
Propanolol
(0.5%)
(lipophilic,
MW 259)
Atenolol (0.5%)
(hydrophilic,
MW 266)
100 (25
) Transcellular Cornea 18.2 18.3 Cornea 46.4
AH 0.97 0.77
Sclera 4.16 5.55 Sclera 57.9
Conjunc. 10.8 16.9
50 Paracellular Cornea 3.80 7.61 ND
AH 0.16 0.44
Sclera 2.78 2.35
Conjunc. 7.53 16.3
a
Nipradilol (1%)
(lipophilic,
MW 326)
100 (11
) Transcellualr Cornea 34.34 – ND
AH 2.85 –
VH BLQ –
Retina
Equator-1.67
Posterior-0.14
Periocular tissue
Equator-1.78
Posterior-0.21
(+Cornea) indicates access of the drop to the cornea, (−Cornea) indicates drop excluded from
cornea for Inulin and Timolol, (+EDTA) indicates the addition of EDTA as a corneal epithelial
penetration enhancer for propranolol and atenolol. Data taken from Ahmed and Patton (
Ahmed et
al. (1987); Chung et al. (1998); and Mizuno et al. (2009)
1985);
%F % oral bioavailability; AH aqueous humor; VH vitreous humor; BLQ below limit of quantitation;
ND not done
a
Post hepatic bioavailability
Drug administered in this manner was also denied lateral diffusion across the anterior ocular surface and access to the conjunctiva. Thus, any drug access to ocular
tissues is by way of corneal penetration into the aqueous humor of the anterior
chamber. It is surprising to note that when Inulin and Timolol are delivered to the
cornea using this chamber, drug levels in the aqueous humor are similar despite
their differences in trans-cellular vs. para-cellular uptake, and a greater than 15-fold
difference in molecular weight (Table 5.1). Drug introduced onto the ocular surface
outside the chamber was capable of diffusion across the conjunctiva, where it gained
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access to periocular space and could potentially diffuse across the posterior sclera
to the retina. Drug administered in this manner showed very low levels in the aqueous humor, and suggests corneal permeability is required for significant aqueous
humor concentrations.
5.2.2 Studies of Trans-Corneal and Periocular Drug Delivery
to the Retina
The periocular route: Several studies on beta-adrenergic receptor blockers (e.g.,
Propranolol, Atenolol, Timolol, and Nipradilol) provide insight on the transit of
drug from ophthalmic drops to the retina. In the case of Timolol, restricting the
application of a 14C radiolabeled derivative to the corneal surface using the Patton
chamber led to rapid penetration across the corneal epithelium and accumulation in
the aqueous humor. This did not result in therapeutically significant levels of Timolol
in either the vitreous or posterior segments, indicating that neither the trans-vitreous
nor the uvea-scleral trans-corneal routes were significant for Timolol. However,
drug applied on the conjunctiva was shown to rapidly diffuse across the conjunctiva
to gain access to periocular fluid and the posterior sclera. Timolol levels in the cornea and aqueous humor were significantly less when the drug solution was denied
contact with the cornea surface. These results support the periocular trans-scleral
route as the predominant route for Timilol transit to the back of the eye, and that
drug distribution via this path can be rapid.
More recently, in a study in rabbits using both radiolabeled and unlabeled drug,
the distribution of Nipradilol (an analog of Atenolol, Propanalol, and Timolol) was
studied following administration as an ophthalmic drop, sub-tenon injection and an
injection into the aqueous humor (Mizuno et al. 2009). With the ophthalmic drop,
drug rapidly appeared at high levels in the cornea, conjunctiva, and aqueous humor
compartments. Drug also rapidly distributed at lower levels into periocular tissues
encompassing the entire eye, and appeared in retinal/choridal tissues at levels
>100 nM within 20–60 min; however, it was undetectable in the vitreous at these
time points. This drug distribution pattern excludes trans-vitreous uptake into the
posterior tissues. In addition, the drug injected into the aqueous humor remained at
high levels in the anterior chamber and cornea, but did not distribute into the posterior vitreous or retinal space, and thus discounts the uvea-scleral route of distribution of Nipradilol to these compartments. Drug from the sub-tenon injection did
appear at significant levels in the retinal/choroidal space but was below the limit of
detection in the vitreous, anterior chamber, and cornea. Consequently, it appears
that while Nipradilol reaches the cornea and anterior chamber via the trans-corneal
route, it reaches posterior retinal tissues via the periocular trans-scleral route.
The trans-vitreous route: This route has proven difficult to separate from the periocular route demonstrated for the beta blockers noted above. No clear data exists for
a study with the use of the Patton chamber to assure corneal dosing.
Brimonidine is an a
pressure and neurodegenerative aspects of glaucoma. Brimonidine has been detected
-adrenergic agonist for the treatment of both the intraocular
2
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5 Topical Drug Delivery to the Back of the Eye
Lower bulbar
conj
Aqueous
humor
Ciliary
body Choroid/retina
Vitreous
humor Blood
Rabbit 0.5%, BID,
14 days
8.39 0.842 63.9 20.8 0.124 0.015
Cyno 0.5%, BID,
14 days
56.2 0.326 32.7 29.3 0.061 0.012
https://t.me/med1917
Table 5.2 Maximum tissue concentrations of brimonidine (mg/g)
in the tissues of the anterior and posterior segments following administration of an
ophthalmic drop to the anterior ocular surface (Table 5.2). In monkeys and rabbits
dosed with 14C-labeled drug, high levels are achieved in the choroid/retina after
single or multiple doses (Acheampong et al. 2002). Systemic drug levels resulting
from topically applied drug were low compared to ocular tissue levels in both
species. In addition, drug levels in the treated eye were significantly higher than that
in the untreated eye in rabbits (Cmax vitreous: 49.3 vs. 2.0 nM). These data are suggestive of a local route of transit of Brimodine to posterior tissues. Pharmacokinetic
analysis indicates that the drug reaches its maximum concentration first at the ocular
surface and aqueous humor, followed by the vitreous and finally the retina/choroid.
This is consistent with a trans-vitreous trans-corneal delivery of drug to the retina
via an ophthalmic drop. While drug concentrations follow the anticipated concentration gradient from corneal surface to aqueous humor and vitreous, the tissue levels
of Brimonidine in the retina/choroid are more than ten times higher than in the vitreous. This is inconsistent with a trans-vitreous trans-corneal uptake but may result
from high levels of melanin binding in the pigmented retinal/choroidal tissues or a
periocular trans-scleral distribution route. Studies in humans undergoing an elective
vitrectomy reveal drug levels in the vitreous were similar to that seen in monkeys
(Kent et al. 2001). Levels in the vitreous of aphakic patients were noted to be significantly higher than normal subjects and may indicate that the lens is a significant
barrier to trans-vitreous trans-corneal distribution of drug to the retina.
A recent study in rats using high concentrations (i.e., 0.1 M) of a 14C-labeled
immunomodulator SAR 1118 demonstrated both a concentration gradient across
tissues from the ocular surface through the aqueous and vitreous compartments to
the retina/choroid and concentration time profile consistent with a trans-vitreous
trans-corneal route of delivery to the retina (Rao et al. 2010).
5.2.2.1 The Uvea-Scleral Route
Studies with radiolabeled albumin injected into the anterior segment of a cynomologous monkey demonstrated that the uvea-scleral outflow of the contents of the
aqueous humor can be enhanced by modulation of the ciliary muscles with topical
application of the prostaglandin PGF2a-1 isopropyl ester. Radiolabeled albumin
appeared in the suprachoroidal space and transited to the ocular posterior pole
within 2 h of administration (Stjernschantz et al. 1999; Alm and Nilsson 2009).
Similar results have been observed in aged human eyes scheduled for enucleation
(Bill and Phillips 1971). It has been suggested that prostaglandins secreted in
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T. Gadek and D. Lee
N
N
N
Timolol
Nipradilol
Brimonidine
ATG-3 (Mecamylamine)
Memantine
AL-8309B
OT 551
SAR 1118
structure not
disclosed
TG100572 R=H
TG100801 R=PhCO
N
N
N
N
N
H
H
N
N
N
N
N
N
N
N
N
N
N
R
O
O
O
CI
O
O
2
NO
N
O
O
O
+
O
O
N
N
Br
N
S
O
O
O
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Fig. 5.2 Structures of drugs delivered to back of eye
inflammatory conditions may enhance drug penetration to the posterior segment via
the uvea-scleral route. Thus, topically applied drug which has penetrated into the
aqueous humor can transit to the posterior segment via the uvea-scleral route, and
potentially access choroid and retina. While it is presently unclear whether all molecules which progress down the uvea-scleral route do so via the suprachoroidal
space, it is clear that this path exists. Molecules progressing along the uvea-scleral
route are subject to vascular absorption and clearance into the systemic circulation.
This clearance route will most likely affect small molecules more than proteins
(Stjernschantz et al. 1999; Alm and Nilsson 2009) (Fig. 5.2).
5.3 Eye Drops for Posterior Segment Diseases in the Clinic
The following discussion presents published data for drugs formulated as ophthalmic
drops in clinical development, and for which there is data indicating that drug is
reaching the posterior site of action via one or more of the transit routes described
above. It is presently not possible to sample drug levels in most human ocular compartments without removal of the eye; however, one can sample aqueous and vitreous
fluids from patients undergoing elective pars plana vitrectomy or other surgical
procedures, and thus obtain a limited understanding of drug distribution patterns in
ocular tissues. Emerging technological developments in confocal and laser microscopy utilizing dual photon excitation may make it possible to noninvasively measure
drug pharmacodynamics and PK in anterior and posterior segments of the human
eye in the future (Wang et
al. 2010). Presently, our understanding of drug distribution
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in the eye is mainly limited to studies in preclinical animals. In the examples described
below, there is a detailed understanding of preclinical ocular PK and tissue distribution, which has yielded insight into the mechanisms of drug transit to posterior
tissues. Though it is often challenging to delineate a transit path for a particular asset
as being trans-vitreous trans-corneal, uvea-scleral trans-corneal, or periocular transscleral, the data is often suggestive of one route being a major contributor.
TG100801 is a dual inhibitor of VEGFR and Src kinases put into clinical development for the treatment of choroidal neovascularization (CNV) due to AMD
http:\\www.clinicaltrials.gov NCT00509548). It possesses a strong preclinical
(
package of data which supports the ability of the drug to reach the back of the eye.
In a series of publications, TargaGen (Doukas et al. 2008; Palanki et al. 2008;
Scheppke et al. 2008) has demonstrated that TG100801 is active in animal models
of retinal disease when administered as eye drops. TG100801 is an inactive pro-drug
of TG100572, which is rapidly hydrolyzed by esterases in ocular tissues. When a
single eye drop (10 mL 0.7% w/v) was applied to a mouse eye, both compounds
yielded measurable levels of TG100572 in the sclera, choroid, and retina, but the
pro-drug delivered tenfold higher levels of drug to the retina (35 h mg/mL of
TG100572 from TG100801 vs. 3.2 h mg/mL TG100572) and sustained drug levels in
all tissues for longer periods. In addition, similarly high levels of pro-drug were measured in the retina, and suggests that the higher retinal levels of drug may be due to
increased penetration of the pro-drug through the retinal pigment epithelium. This
trend is supported by the higher lipophilicity of the pro-drug. Plasma levels were
undetectable (<1 ng/mL) at all timepoints. Qualitatively similar results were obtained
in rats, though the conversion of TG100801 to TG100572 appeared to be slower.
The PK of TG100572 and TG100801 were also evaluated in rabbits, a larger
species whose eye size and geometry more closely mimics human eyes. As in rodents,
significant concentrations are delivered to the sclera/choroid/retina tissues. Relative
to these drug levels, very little drug was measured in aqueous humor and lens, with
intermediate levels measured in the vitreous. This suggests that the trans-corneal
routes are not the major paths for drug transit. A radiotracer study with 14C-TG100801
confirms the local nature of the delivery to the posterior eye and absence of significant systemic exposure or distribution to the fellow eye (Struble et al. 2007).
In a mouse laser CNV model in which CNV was induced by laser irradiation in
both eyes, treatment of one eye with TG100801 reduced the size of the lesion relative
to a vehicle-treated eye. The untreated fellow eye showed no effect, and strongly suggests that the treated eye effects were via local, rather than systemic delivery of drug.
Whereas the laser CNV model is a measure of the drug’s activity at the choroid, a
VEGF-induced retinal leak model is used to assess the ability of drug to access the
retina. TG100801 (1.22% w/v, q.d.) completely abolished the retinal leak. The totality
of data for TG100801 (efficacy via local delivery, low aqueous humor drug levels)
suggests that it reaches the retina via the periocular trans-scleral route.
ATG-3 is a topical eye drop formulation of Mecamylamine (broad spectrum
mAChR antagonist) under development by Comentis for wet AMD. In a 16-week
Ph I/II trial for diabetic macular edema (Campochiaro et al. 2010), results suggested
that 8/21 patients showed convincing improvements in best corrected visual acuity
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