Penetracion Ocular

Molecular Design for Enhancement of Ocular Penetration
YOSHIHISA SHIRASAKI
Senju Pharmaceutical Co., Ltd., 1-5-4 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan
Received 22 June 2007; revised 21 August 2007; accepted 23 August 2007
Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21200
ABSTRACT: Over the past two decades, many oral drugs have been designed in
consideration of physicochemical properties to attain optimal pharmacokinetic proper-
ties. This strategy signicantly reduced attrition in drug development owing to inade-
quate pharmacokinetics during the last decade. On the other hand, most ophthalmic
drugs are generated from reformulation of other therapeutic dosage forms. Therefore,
the modication of formulations has been used mainly as the approach to improve ocular
pharmacokinetics. However, to maximize ocular pharmacokinetic properties, a specic
molecular design for ocular drug is preferable. Passive diffusion of drugs across the
cornea membranes requires appropriate lipophilicity and aqueous solubility. Improve-
ment of such physicochemical properties has been achieved by structure optimization or
prodrug approaches. This review discusses the current knowledge about ophthalmic
drugs adapted from systemic drugs and molecular design for ocular drugs. I propose the
approaches for molecular design to obtain the optimal ocular penetration into anterior
segment based on published studies to date. 2007 Wiley-Liss, Inc. and the American
Pharmacists Association J Pharm Sci 97:24622496, 2008
Keywords: tissue partition; drug design; permeability; solubility; structure-property
relationship (SPR); epithelial delivery/permeability
INTRODUCTION
Over the past two decades, oral drugs have been
designed in consideration of physicochemical
properties to maximize their pharmacokinetic
properties. Numerous papers and reviews
describe the design of molecules to improve the
pharmacokinetic properties such as oral absorp-
tion, bioavailability and the duration of action.
19
At present, in silico screening is widely used for
the selection of drug-like compounds from combi-
natorial libraries and is based on physicochemical
parameters such as the rule-of-ve,
10
which is a
qualitative absorption/permeability predictor.
1113
Physicochemical property-based drug design
can reduce attrition due to inappropriate phar-
macokinetics in the drug development process.
Inappropriate pharmacokinetics accounted for
Abbreviations: 17-Ph-PGF2
a
, 17-phenyl-18,19,20-trinor
prostaglandin F2
a
; 17-Ph-PGF2
a
-IE, isopropyl ester of 17-Ph-
PGF2
a
; ACD log D
7
, distribution coefcient in pH 7 was calcu-
lated using ACD/Labs software; API, active pharmaceutical
ingredient; AUC, area under the tissue concentration-time
curve; BBB, blood brain barrier; BCRP, breast cancer resistant
protein; Caco-2, human colon adenocarcinoma cells; CAI, car-
bonic anhydrase inhibitor; C
max
, maximum observed concentra-
tion in tissues after instillation; CNS, central nervous system;
EGTA, ethylene glycol-bis(2-aminoethylether)-N,N,N
0
,N
0
-tetra-
acetic acid; FDA, U.S. Food and Drug Administration; ICB, iris-
ciliary body; IOP, intraocular pressure; LAT, large neutral
amino acid transporter; log D
xx
, logarithm of n-octanol/buffer
distribution coefcient at pH xx; log P, logarithm of n-octanol/
water partition coefcient; MDCK, MardinDarby canine
kidney cells; MDR, multidrug resistance protein; MP, melting
point; MRP, multidrug resistance-associated protein; NSAID,
nonsteroidal anti-inammatory drug; P
app
, apparent corneal
permeability coefcient; PepT1, intestinal peptide transporter
1; PGF2
a
, prostaglandin F2
a
; P-gp, P-glycoprotein.
Correspondence to: Yoshihisa Shirasaki (Telephone: 81-
78-997-1010; Fax: 81-78-997-1016;
E-mail: shirasaki@senju.co.jp)
Journal of Pharmaceutical Sciences, Vol. 97, 24622496 (2008)
2007 Wiley-Liss, Inc. and the American Pharmacists Association
2462 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 7, JULY 2008
about 40% of the reasons for attrition in 1992, but
decreased to about 10% in 2000.
14,15
Thus, in oral
drugs, physicochemical-based drug design can
successfully decrease attrition caused by pharma-
cokinetic reasons. On the other hand, in ophthal-
mology, only a few drugs are designed exclusively
for ocular use.
1620
Systemic administration often
results in insufcient ocular drug concentration
because the drug penetration from the blood
stream to the eye tissues is limited by a blood-
aqueous and a blood-retinal barrier located in iris
and retina-choroid, respectively.
21,22
To maximize
drug penetration to the target tissues in parti-
cular the anterior segment of the eye, topical
instillation of eye drops are used mainly in clinical
therapy. The periocular injection methods such as
sub-conjunctival, sub-tenon and intravitreal
injection can attain high levels of drugs in
intraocular tissues, but they are invasive and
inconvenient.
23
Therefore topical instillation is
the most useful method because it delivers the
drug easily and noninvasively to the external and
intra ocular tissues.
Ophthalmic drugs in current use originate from
oral drugs mainly because the adaptation of oral
drugs to ophthalmic drugs is very efcient in drug
developments. However, most oral drugs gener-
ally have low aqueous solubility for ophthalmic
solutions. The ocular bioavailability of eye drops is
generally low,
21
so high aqueous solubility is
desirable for eye drops to attain the high drug
concentration in the formulation, unless it pro-
duces toxicity such as ocular irritation and
hyperemia. An alternative option is suspension
formulation but this is accompanied with pro-
blems such as inconvenience and technical
difculties in manufacturing processes. Ophthal-
mic suspensions need to be resuspended when
they are administered. The active pharmaceutical
ingredients (API) of an ophthalmic suspension
have to be sterilized. Since most APIs for injection
have enough aqueous solubility as formulate eye
drops and are sterilized, such difculties would
not be problematic. However, the majority of them
is unstable in an aqueous solution for a long time
and often has low lipophilicity, which may lead
to low corneal permeability. Because ocular bio-
availability depends mainly upon pharmaceutical
formulation, the modication of formulations has
so far been used as the major approach to improve
the ocular pharmacokinetics of eye drops.
24
However, if the drug only has poor corneal
permeability and aqueous solubility, it is difcult
to deliver sufcient amounts of drugs to intrao-
cular target tissues using the modication of
formulation. Therefore, the molecular design with
consideration of ocular pharmacokinetic and phy-
sicochemical properties is desirable for ophthal-
mic drugs to obtain optimal ocular bioavailability
and efcacies.
This review summarizes the current state of
knowledge about molecular design for ocular
drugs and compounds for ophthalmic use origi-
nating from systemic drugs. I will also consider
the molecular design to maximize the penetration
into the anterior segment based on published
studies to date.
ABSORPTION ROUTE OF DRUG AFTER
TOPICAL OCULAR ADMINISTRATION
Various anatomic and physiologic barriers limit
the drug absorption to the anterior segment of the
eye (cornea, aqueous humor, iris, ciliary body and
lens). The structure of the eye is shown in
Figure 1. In general, only 17% of the dose of
the drugs after topical instillation is able to attain
the aqueous humor.
24
The instilled drug is diluted
by tear uid and rapidly removed from the ocular
surface by tear turnover and blinking. These
resulted in only a short contact time on the ocular
surface. The large fraction of the instilled drug
will be transferred to systemic circulation via the
nasolacrimal duct in a few minutes. In the case of
lipophilic drugs (log P>0), more than 5080% of
instilled doses are absorbed into the systemic
circulation.
25
Figure 1. Cross sectional view of the eye.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 7, JULY 2008
DESIGN FOR ENHANCEMENT OF OCULAR PENETRATION 2463
The drug in tear uid is absorbed via two routes:
corneal route and noncorneal route (conjunctiva-
sclera route).
24
Most drugs penetrate to the cornea
via transcellular absorption as a major route,
because the corneal epithelium cells form tight
junctions that limit paracellular drug permea-
tion.
21
The drugs pass through the conjunctiva
and the sclera via not only transcellular absorp-
tion, but also paracellular absorption, because
these tissues are more leaky than the cornea. The
permeability of drugs via transcellular absorption
depends mainly on lipophilicity. Most ophthalmic
drugs with modest lipophilicity and low-molecular
weight are predominately absorbed via the
corneal route. Animal studies of topical instilla-
tion have shown that corneal route/noncorneal
route ratio is 70:1, 12:1, and 5:1 in the case of
hydrocortisone, timolol and pilocarpine, respec-
tively.
26
Therefore, it is considered that the cornea
is the most principle route for ocular drug
penetration from tear uid to the anterior
segment.
The cornea is very tight tissue, more than the
intestine, lung, bronchus, and nasal mucosa, and
the drug penetration is difcult.
27
The cornea is
composed of ve membranes: epithelium, Bow-
mans membrane, stroma, Desmets membrane,
and endothelium. Among these layers, epithe-
lium, stroma, and endothelium are the substan-
tial barriers. The corneal epitheliumis a lipophilic
membrane, which forms tight and gap junctions,
and the most prominent barrier for corneal
absorption.
28
Therefore, most of the lipophilic
compounds can pass through the corneal epithe-
lium via transcellular absorption. Recent studies
show that various uptake and efux trans-
porters such as oligopeptide transporters, amino
acid transporters, monocarboxylate transporters,
nucleoside transporters, P-glycoprotein (P-gp,
MDR1), MRP1MRP6, and BCRP are expressed
in cornea epithelium and actively uptake and
efux their substrates.
21,2934
The stroma is in
hydrophilic environment and limits the pene-
tration of highly lipophilic or large molecular
weight compounds. The endothelium is a leaky
lipophilic barrier and partially resists the pene-
tration of lipophilic compounds, but not hydro-
philic compounds.
In the case of the conjunctiva-sclera route,
drugs can be directly accessed to iris and ciliary
body through conjunctiva and sclera without
diffusion to aqueous humor. The conjunctiva is
a mucous membrane and has many capillary blood
vessels. The area of human conjunctiva is
approximately 17-fold larger than that of the
cornea.
26
The conjunctival epithelium forms tight
junction and limits drug penetration. In conjunc-
tival epithelium, expression of efux transporters
such as P-gp has been reported.
26
The sclera,
which is constructed of collagen bundle and elastic
ber, is also a leaky tissue. The scleral perme-
ability of polyethylene oligomer is 2-fold less than
that of conjunctiva and 10-fold more than that of
the cornea. The conjunctiva and sclera are ever
leakier than the cornea and permeate the drugs
through paracellular absorption in addition to
transcellular absorption.
35
The conjunctiva-sclera
route is generally considered as nonproductive
route because the vessels in conjunctiva rapidly
absorbed most of the instilled drug into the
systemic circulation. However, several reports
suggest that the conjunctiva-sclera route is the
main route of penetration to the anterior segment
for carbonic anhydrase inhibitors (CAIs), hydro-
philic compounds and large molecules.
24
EVALUATION OF OCULAR PENETRATION
AND REQUIRED PHYSICOCHEMICAL
PROPERTIES
Corneal Permeability
For the sufcient drug penetration into aqueous
humor, both high corneal permeability and
aqueous solubility are generally required.
36
The
corneal permeability correlates with lipophilicity
like Caco-2 and MDCK cell permeability. It is
reported that the optimal lipophilicity for corneal
permeation is log P 23 in the case of steroids and
b-blockers.
37,38
Excess lipophilicity would lead to
a reduction in permeability of corneal stroma,
which is hydrophilic tissue and limits the pene-
tration of highly lipophilic compounds. The
corneal permeability has been evaluated gener-
ally by using rabbit corneas.
39
The corneal
thickness of rabbits is similar to that of humans.
Good correlation has been observed between
rabbit and human corneal permeability in the
case of both cyclophosphamide
40
and CAIs.
41
The
Ussing chamber usually has been used in the
assessment of corneal permeability. In this
system, the apparent corneal permeability coef-
cient ( P
app
) is calculated.
36
The P
app
value can be
used to evaluate the relative permeability.
Recently, the in vitro cell systems for predicting
corneal permeability are by determination of
permeability of compounds through rabbit, bovine
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 7, JULY 2008 DOI 10.1002/jps
2464 SHIRASAKI
and human corneal epithelium cells.
4247
The
permeability of the corneal epithelium cell sys-
tems is positively correlated with the corneal
permeability. In addition to passive diffusion, the
active transport and metabolism may be partially
evaluated by these systems. The expression of
various transporters
4851
and the enzymes for
ester hydrolysis on corneal cell lines
46,52
has been
reported. These systems may be useful for screen-
ing of compound libraries to predict the corneal
permeability and metabolism.
Aqueous Solubility
The high aqueous solubility is also important
because only the dissolved drug is capable of
permeating cornea membrane. The instilled drug
is diluted by tear uid and contacts with the
cornea in a very short time.
22,24,27,36
The ocular
bioavailability is generally quite low (17%) and
high drug concentration is important for ophthal-
mic solution. Therefore, ophthalmic drugs need
high aqueous solubility in tears at neutral pH
(pH 6.57.6) to permeate across the cornea.
On the other hand, the enhancement of aqueous
solubility may reduce drug lipophilicity and
corneal permeability. Although the incorporation
of a strong ionizable center, such as sulfonate,
phosphate, and guanidine moieties, into a struc-
tural template can provide highly soluble mole-
cules, excessive aqueous solubility would cause a
marked reduction in corneal permeability. The
compounds having ionizable centers should be
designed not to have excess ionic strength at
physiological pH. After all, it is desirable to
possess adequate aqueous solubility without loss
of lipophilicity for corneal penetration. An excep-
tion to this is ampholyte CAI, which show higher
permeability at the higher rate of the ionic species.
The ionic form more readily sequestered in the
cornea, which led to the higher drug levels in
cornea, aqueous humor and iris-ciliary body than
the unionized form.
53
Assessment of Intraocular Penetration
In vivo ocular pharmacokinetic studies for asses-
sing intraocular penetration have most commonly
been performed with rabbits, because the rabbits
have relatively large eyeballs in spite of their
small bodies.
39
The corneal permeability for
lipophilic compounds in rabbits is approximately
equivalent to that in humans, but when the same
dosage is topically administrated, intraocular
drug concentration in rabbits is often higher than
that in humans. The faster precorneal loss of
instilled ophthalmic drugs in human ascribed to
blinking with about three times more frequency.
The drug penetration across the cornea is higher
in rabbits than in humans, but it is probable that
rabbits can be used for comparison of intraocular
penetration for a set of compounds. The aqueous
humor drug concentrations and area under the
curve (AUC) can be used as an indicator of
intraocular tissues drug concentration. The drug
concentration in aqueous humor would be easy to
determine due to uid. Aqueous humor contains
only low protein content (0.2 mg/mL) compared to
plasma (50 mg/mL)
54
and is approximated to the
free fraction of drugs in iris and ciliary body
located around the anterior chamber, which parti-
cipates in pharmacodynamic effects in intraocular
tissues. The intraocular drug levels after instilla-
tion would be overestimated when the levels are
obtained in rabbit experiment. Therefore, it is
suggested that several-times higher ocular levels
in rabbit are required for the sufcient efcacy in
human.
55
REPRESENTATIVE EXAMPLES
Representative examples of corneal permeability
and ocular penetration of sets of compounds and
molecular designs for improved ocular pharma-
cokinetics are described below.
Anti-Glaucoma Agents
Carbonic Anhydrase Inhibitors (CAIs)
Oral CAIs such as acetazolamide and ethoxzola-
mide have been used for the treatment of
glaucoma and hyper intraocular pressure (IOP),
but their systemically adverse effects resulted in
the discontinuation of the drugs in about 50% of
patients.
56
Therefore, topical instillation of CAIs
has been investigated. It is expected that topical
instillation of CAIs is capable of providing the IOP
lowering effect without systemically adverse
effects. However, topical instillation of oral CAIs
such as acetazolamide, methazolamide and ethox-
zolamide, did not show sufcient efcacy. For the
IOP lowering effect, CAIs have to reach the ciliary
process where aqueous humor is produced by
carbonic anhydrase. To deliver CAIs to the ciliary
process, ocular CAIs need to possess the high
corneal permeability and aqueous solubility,
which lead to high intraocular drug concentration.
Two major approaches have been used for the
design of topical CAIs for eye drops. The
approaches, categorized into ring approach and
tail approach for enhancing ocular penetration,
have been tried to obtain the topically effective
CAIs.
5759
The ring approach implies that a
modication of ring system of lipophilic oral CAIs
such as ethoxzolamide will improve the aqueous
solubility. Two topical CAIs presently available
(dorzolamide
18
and brinzolamide)
60
were design-
ed by this approach. On the other hand, in the tail
approach, the functionalities, which can enhance
corneal permeability and aqueous solubility, are
attached to the ring of oral CAIs such as
acetazolamide and methazolamide without mod-
ication of the ring.
Ethoxzolamide, an oral CAI, shows high corneal
permeability, but its aqueous solubility is very
low.
61
The low solubility resulted in insufcient
intraocular tissue drug concentration for the
efcacy after topical instillation of aqueous
suspension. To improve its poor properties, Merck
Research Laboratories group has designed and
synthesized many CAI inhibitor for topical instil-
lation based on ethoxzolamide using the ring
approach.
57
Finally, they identied a topical CAI,
dorzolamide, which is approved as the rst topical
CAI from FDA. The physicochemical and ocular
pharmacokinetic properties of several examples of
these CAIs are shown in Table 1.
The Merck group focused on conversion of 6-
position functionalities on ethoxzolamide. The
conversion of the ethoxy group into the hydroxy
group led to an increase in aqueous solubility, and
this phenol L-643,799 demonstrated a weak IOP
lowering effect in a rabbit model.
61
Since this
conversion lowered the corneal permeability,
L-643,799 was esteried to the corresponding
O-pivaloyl derivative L-645,151 to increase cor-
neal permeability like dipivefrine
62
(dipivaloyl
ester prodrug of epinephrine).
63
This compound is
efcacious in rabbits, but its repeated instillation
for 3 months induced ocular irritation. This may
be due to a drug mediated allergic reaction caused
by the formation of an allergen generated by a
reaction between the reactive sulfamoyl group at
2-position on the benzothiazole ring and biomo-
lecular nucleophiles. Thus, less reactive ben-
zothiophene analogs have been synthesized.
64
The lipophilicity of the benzothiophene derivative
L-650,719 is similar to the corresponding ben-
zothiazole derivative L-643,799. The area under
the curve of the time-drug concentration prole
in aqueous humor (AUC) after instillation for
benzothiophene phenol L-650,719 is approxi-
mately equal to that for L-643,799.
65
The acetyl
analog of L-650,719 (L-651,465) showed roughly
twofold higher AUC than the pivaloyl analog of
L-643,799 (L-645,151). Even though the benzo-
thiophenes and benzothiazoles show relatively
high aqueous solubility, they were only formu-
lated as suspension at 12%, not ophthalmic
solution. Thus, the discovery of compounds with
aqueous solubility exceeding 1% was continued
and the efforts led to the thienothiopyran
derivative L-654,230 with more than 1%solubility
at pH 7.4.
66
The 4-hydroxy-thienothiopyran L-
654,230 showed the 8.1 mg/g of C
max
after topical
instillation in iris-ciliary body (ICB) of pigmented
rabbits far exceeded the values of benzothiazole
L-645,151 and benzothiophene L-651,465. The
conversion of the benzothiophene ring into
the 5,6-dihydro-4H-thieno[2,3-b]thiopyran 7,7-
dioxide ring greatly increased aqueous solubility
without the loss of adequate lipophilicity. The
substitution of 4-OH functionality in L-654,230
with isobutylamine moiety provided MK-927 with
higher C
max
value in ICB than alcohol L-
654,230.
67
This increase in C
max
value in ICB is
most likely ascribed to its basic functionality,
which increases the binding afnity for melanin.
The further modication of MK-927 identied
dorzolamide, which demonstrated the similar
drug levels in ICB after instillation and was
approved for the treatment of glaucoma by FDAin
1994.
57,58
Thereafter, brinzolamide, which is a
6-(methoxypropyl)aza analog and is more lipo-
philic structure than dorzolamide, also received
FDA approval in 1999 as an anti-glaucoma
agent.
60
The compound shows lower solubility
at neutral pH than dorzolamide and formulated
as an aqueous suspension. The drug levels of
brinzolamide are lower than that of dorzolamide,
but showed the longer duration of the action with
the approximately same efcacy as dorzolamide.
This longer duration may be attributed to the
suspension formulation and the increase in
lipophilicity caused by the introduction of the
methoxypropyl group.
The tail approach consisted of modifying the
side chains of well-known oral aromatic/
heterocyclic sulfonamide derivatives, such as
acetazolamide and its N-methyl derivative metha-
zolamide, to improve the physicochemical and
ocular pharmacokinetic properties.
58,59,68
These
examples are shown in Table 2. Scozzafava et al.
69
2466 SHIRASAKI
obtained the topical effective CAIs with high
intraocular penetration better than dorzolamide
by attaching tails such as protonable nitrogen
atom (EGTA, 2,3-pyridinedicarboxyimido,
70
gua-
nidino,
71
and pycolinoyl
72
) and peruoroalkyl/
aryl moieties,
73
which provided the molecules
adequate lipophilicity and aqueous solubility. The
condensation of 2,6-pyridinedicarboxy acid with
the C4-amino ethyl group in dorzolamide yielded
the ocularly permeable CAI with higher intrao-
cular drug levels than dorzolamide.
70
Sharir
et al.
74
reported that the acetyl group of acet-
azolamide was substituted with dicarboxylic acids
such as oxalate, succuinate, adipate and succeed
in increasing corneal permeability and demon-
strating the IOP lowering effect (Tab. 3).
b-Blocker
All ophthalmic b-blocker drugs on the market
have been generated by the reformulation of oral
b-blocker drugs. This class contains various drugs
Table 1. Physicochemical and Ocular Pharmacokinetic Properties of CAI Inhibitors (Ring Approach)
Compound log D
7.4
a
Solubility (mg/mL) C
max
(mg/mL or g)
b
Refs.
Acetazolamide
0.85 0.71 (pH 7.4) 57,60
Ethoxzolamide R
C
2
H
5
, X
N 2.06 (pH 7.2) 0.024 (pH 7.4) 61,66

L-643,799 R
H, X
N 1.11 7.92 (pH 7.65) 2.67/2.21 (AH

c
/ICB
d
)
e
57,61,65
L-645,151 R
COC(CH
3
)
3
, X
N 2.45 0.058 (pH 7.4) 3.91/4.45 (AH

c
/ICB
d
)
e
57,63,65
L-650,719 R
H, X
CH 1.28 1.16/1.44 (AH

c
/ICB
d
)
f
57,64,65
L-651,465 R
COCH
3
, X
CH 1.28 3.05/2.76 (AH

c
/ICB
d
)
f
57,64,65
L-654,230 R
OH 0.35 12.5 (pH 7.4) 8.1 (ICB

d
)
g
57,66,67
MK-927 R
NHCH
2
CH(CH
3
)
2
0.90 >20 (pH 7.4) 27.8 (ICB
d
)
g
57,67
Dorzolamide (L-671,152)
0.18 6.7 (pH 7.4) 7.8/27.0 (AH
c
/ICB
d
)
g
18,57,60
Brinzolamide (AL-4623A)
0.50 (pH 7.4) 3.85 (ICB
d
)
h
60
a
Distribution coefcient in pH 7.4.
b
The C
max
after topical instillation.
c
Aqueous humor.
d
Iris-ciliary body.
e
2% suspension.
f
0.5% suspension.
g
2% solution.
h
1% suspension.
with diverse physicochemical properties. Among
these drugs, the major ophthalmic drugs are
timolol, levobunolol, betaxolol, metipranolol, car-
teolol, and so on.
75
Corneal permeability and
ocular pharmacokinetics of various oral b-block-
ers has been evaluated. The lipophilicity and
pharmacokinetic parameters of these drugs are
included in Table 4. Schoenwald et al. investi-
gated the correlations between lipophilicity and
corneal permeability of 12 b-blockers.
38
This
study revealed that the corneal permeability
and lipophilicity (log D
7.65
) exhibited a parabolic
relationship having the optimal log D
7.65
at about
2.5 (Fig. 2). An increase in lipophilicity of the
compound enhances the permeability to the
cornea epithelium, whereas it does not increase
the permeability to the corneal stroma due to its
hydrophilic environment.
76
Wang et al.
77
also
investigated the relationship between corneal
permeability and lipophilicity of 13 b-blockers.
This study demonstrated that the corneal perme-
ability varied with lipophilicity according to a
sigmoidal relationship and was saturated at about
log P3. However, acebutolol was an outlier in
Table 2. Physicochemical and Pharmacokinetic Parameters After Topical Instillation of CAI Inhibitors
(Tail Approach)
Compound
log D
7.4
(CHCl
3
)
a
Sol
b
(mM)
(pH 7.4) k
in
c
(10
3
h
1
) C
1h
/C
2h
d
(mM)
c
Refs.
Acetazolamide (COCH
3
) 0.001 3.2 0.37 70
1.45 52 4.6
268/53 (AH),
59/37 (CP)
69
0.449 81 (HCl) 3.8
280/42 (AH),
50/12 (CP)
70
1.620 73 4.1
308/50 (AH),
54/18 (CP)
71
1.944 75 4.7 325/45 (AH), 69/21 (CP) 71
0.589 78 (HCl) 2.7
283/39 (AH),
51/10 (CP)
72
2.113 62 4.5
324/42 (AH),
45/13 (CP)
73
Dorzolamide 2.0 60 (HCl; pH 5.8) 3.0 32/21 (AH), 15/6 (CP) 73
a
Distribution coefcient between chloroform and buffer in pH 7.4.
b
Aqueous solubility.
c
The rate constant of transfer across the cornea.
d
Drug concentration in aqueous humor and ciliary process at 1 and 2 h following instillation of 2% solution.
2468 SHIRASAKI
these reports. Its corneal permeability was lower
than the value expected fromits log Pand log D
7.65
(Fig. 2). Recently, Kawazu et al.
78
suggest that
acebutolol is actively secreted via P-gp, an active
efux transporter, in corneal epithelium. The
presence of the amide moiety in acebutolol, which
is a hydrogen bond donor, may contribute to not
only a decrease in passive diffusion, but also an
increase in afnity to P-gp.
79
The enhanced lipophilicity results in an
increase of corneal permeability, but this does
not always lead to high C
max
and drug exposure in
aqueous humor after instillation. Huang et al.
80
compared the penetration of three b-blockers,
bufuralol, timolol and acebutolol, into aqueous
humor. Ros et al.
81
also investigated the drug
exposure of four b-blockers: atenolol, timolol,
propranolol, and metoprolol. Both studies
revealed that timolol showed higher AUC values
than the more lipophilic compounds bufuralol and
propranolol.
80,81
The lipophilic nature of these
drugs led to the wide tissue distribution and
lowered the aqueous humor drug levels. The less
IOP reducing efcacy of propranolol relative to
timolol may be due to the low unbound fraction
caused by high lipophilicity.
82
Accordingly, the 3-
morpholino-1,2,5-thiaziazole structure of timolol
would contribute to adequate corneal permeabil-
ity and high free drug levels because of the
addition of both appropriate lipophilicity and
aqueous solubility to the molecule. On the other
hand, acebutolol showed low aqueous humor drug
levels as expected from its corneal permeability.
The log P value of levobunolol (log P2.4),
which is one stereoisomer of bunolol, is higher
than that of timolol (log P1.91) and lower than
that of propranolol (log P3.21). Levobunolol and
bunolol demonstrated slightly higher AUC values
in an aqueous humor relative to timolol and
propranolol.
8385
Levobunolol and bunolol were
rapidly converted in the cornea to an active
metabolite dihydrobunolol more than 80% at 1 h
after instillation by the reduction of the keto
group. Levobunolol or bunolol are in lipophilic
intact forms when they permeate the corneal
epithelium. Then, they are transformed in the
cornea to dihydrobunolol, which is less lipophilic
and shows a longer half-life compared to the
parent form. Due to this, bunolol may show the
higher total aqueous drug levels (buno-
lol dihydrobunolol) than timolol.
To enhance corneal permeability, ester pro-
drugs of several b-blockers (such as timolol and
tilisolol) have been synthesized by O-acylation
with aliphatic short chain fatty acids at a-hydroxy
group (Tab. 5).
17,86
Timolol ester prodrugs showed
parabolic relation ships between lipophilicity and
both the corneal permeability (Fig. 3) and the drug
levels in aqueous humor at 20 min after instilla-
tion (Fig. 4). The optimal log D
7.4
value of the ester
prodrug as well as the nonprodrug b-blockers was
estimated as approximately 2.5. Both the corneal
permeability and the drug levels in aqueous
humor of O-pivaloyl ester prodrug were lower
than the values expected from its lipophilicity
because its hydrolysis rate was slower than that of
linear ester prodrugs. Ester prodrugs are con-
verted mainly in corneal epithelium to the parent
compound that is less lipophilic than the pro-
drugs. The reduced lipophilicity caused by the
corneal hydrolysis may lead to an increase in
unbound fraction in ocular tissues. Therefore,
Table 3. Physicochemical and Pharmacokinetic Parameters After Topical Instillation of Acetazolamide
Biscarbonylamides (Tail Approach)
74
Compound log D
7.4
(Et
2
O)
a
Solb (mg/mL)
b
(pH7.4) k
in
(10
3
h
1
)
c
C
1h
(mM) (CP/AH)
d
R
H >18 0.3
R
COCH
3
(acetazolamide) 0.85 1.8 2.0
R
COCO
2
C
2
H
5
1.00 25 3.2 176/53
R
CO(CH
2
)
2
CO
2
C
2
H
5
0.305 1.8 15.2 62/38
R
CO(CH
2
)
4
CO
2
C
2
H
5
0.144 0.17 48.4 19/4.8
a
Distribution coefcient between diethyl ether and buffer in pH 7.4.
b
Aqueous solubility.
c
The rate constant of transfer across the cornea.
d
Drug concentration in ciliary process and aqueous humor at 1 h following instillation.
Table 4. Physicochemical and Ocular Pharmacokinetic Properties of b-Blockers
Compound log P
ACD
log D
7
a
P
app
b
(10
6
cm/s)
C
max
c
(mg/mL)
AUC
c
(mg h/mL) Refs.
Penbutolol 4.15 2.05 45 38,76
Bufuranol 3.65 1.43 57 22.86
(Ref. 80)
10.1
(Ref. 80)
38,76,80
Betaxolol 3.44 0.56 27 77
Propranolol 3.21 1.00 48 5.32
(Ref. 81)
3.80
(Ref. 81)
38,76,81
Alprenolol 2.37 0.77 29 38,77
Levobunolol 2.40 0.77 16
(Ref. 76),
23
(Ref. 77)
5.92
(Bunolol)
(Ref. 83)
4.56
(Bunolol)
(Ref. 83)
38,76,
77,83
Oxprenolol 2.37 0.17 25 (Ref. 76),
32 (Ref. 77)
38,76,77
Metoprolol 1.88 0.33 22
(Ref. 76),
28
(Ref. 77)
2.89
(Ref. 81)
2.01
(Ref. 81)
38,76,
77,81
Timolol 1.91 1.77 12
(Ref. 76),
12
(Ref. 77)
30.65
(Ref. 80),
5.86
(Ref. 81)
25.4
(Ref. 80),
3.73
(Ref. 81)
38,76,77,
80,81
(Continued)
2470 SHIRASAKI
prodrugs might be superior in pharmacological
activity to nonprodrugs ascribed to the presence of
much free fraction. Conversion to aliphatic acid
ester prodrugs of tilisolol, a hydrophilic b-blocker,
also provided an improved corneal permeability
and intraocular penetration. The propionyl and
butyryl ester prodrugs demonstrated approxi-
mately sixfold higher tilisolol concentration at
1 h after instillation in aqueous humor than the
parent compound.
87
Oxime/methoxime analogs of b-blocker have
been reported as classes of prodrugs, except for
esters. Bodor et al. synthesized oxime/methoxime
analogs of alprenolol, betaxolol, carteolol, propra-
nolol, timolol, etc. Some of these compounds
demonstrated higher and longer IOP reducing
efcacy than the parent drugs.
20
For instance,
after instillation the oxime analog of propranolol
Table 4. (Continued)
Compound log P
ACD
log D
7
a
P
app
b
(10
6
cm/s)
C
max
c
(mg/mL)
AUC
c
(mg h/mL) Refs.
Acebutolol 1.77 0.11 0.85
(Ref. 76),
1.1
(Ref. 77)
1.26
(Ref. 80)
2.93
(Ref. 80)
38,76,
77,80
Pindolol 1.75 0.18 10 77
Nadolol 0.93 0.83 1.0
(Ref. 76)
38,76
Atenolol 0.16 2.02 0.67
(Ref. 76)
2.22
(Ref. 81)
0.93
(Ref. 81)
38,76,81
Sotalol 0.62 1.82 1.6
(Ref. 76)
38,76
a
Distribution coefcient in pH 7 was calculated using ACD/Labs software.
b
Corneal permeability.
c
The values in aqueous humor after single
81,83
or triple
80
instillation normalized to 1% solution dosing.
Figure 2. Relationship between logarithm of cor-
neal permeability coefcient ( P
app
) and lipophilicity
(log D
7.65
) in the rabbit intact cornea. This graph was
reconstructed from the graph in Ref. 38.
Table 5. Physicochemical and Ocular Pharmacokinetic Properties of Timolol
86
and Tilisolol Prodrugs
87
Compound log D
7.4
a
P
app
(10
6
cm/s)
b
C
20min
c
or C
1h
d
(mM)
Timolol prodrugs
R
H 0.04 8.1 7.7

c
R
COCH
3
1.1 23 23
c
R
COCH
2
CH
3
1.6 29 19
c
R
CO(CH
2
)
2
CH
3
2.1 32 22
c
R
COC(CH
3
)
3
2.7 13 17
c
R
CO(CH
2
)
3
CH
3
2.7 31 26
c
R
CO(CH
2
)
4
CH
3
3.3 21 21
c
R
CO(CH
2
)
6
CH
3
4.4 8.9 12
c
Tilisolol prodrugs
R
H 0.27 2.7 3.1

d
R
COCH
3
1.02 8.9 4.0 (vs. parent)
d
R
COCH
2
CH
3
1.56 8.4 5.1 (vs. parent)
d
R
CO(CH
2
)
2
CH
3
2.02 15 6.2 (vs. parent)
d
R
CO(CH
2
)
3
CH
3
2.47 13 5.9 (vs. parent)
d
a
Distribution coefcient in pH 7.4.
b
Corneal permeability. The data were constructed from the graph in Ref. 86.
c
Drug concentration in aqueous humor at 20 min after instillation. The data were constructed from the graph in Ref. 86.
d
Drug concentration in aqueous humor at 1 h after instillation.
Figure 3. Relationship between corneal permeability
coefcient ( P
app
) and prodrug lipophilicity (log D
7.4
) in
the rabbit intact cornea. This graph was reconstructed
from the graph in Ref. 86.
Figure 4. Relationship between aqueous humor
timolol concentration at 20 min and prodrug lipophili-
city (log D
7.4
) in the rabbit intact cornea. This graph was
reconstructed from the graph in Ref. 86.
2472 SHIRASAKI
showed higher intraocular penetration and longer
duration of action by sustainable release of the
parent drug (Tab. 6).
88
Since release of parent
compound for oxime/methoxime analogs is slower
than that of ester prodrugs, conversion to oxime/
methoxime is useful for continuation of the
duration of action.
In the case of b-blockers that possess relatively
low lipophilicity and hydrophilic functionalities,
such as hydroxyl and secondary amine group,
increasing lipophilicity of the molecule would
improve the ocular penetration. However, exces-
sive lipophilicity would cause an increase in
ocular tissue binding, leading to a decrease in
unbound fraction and an increase in resistance
to hydrophilic corneal stroma. For this reason,
the highly lipophilic molecule is unsuitable for
ocular drugs as ophthalmic solution. It is most
likely to be effective for ocular drugs to in-
troduce a heterocycle, which allows the molecules
to increase lipophilicity without loss of water
solubility. The ester prodrug approach is also
desirable because the molecule will be converted
into the less lipophilic parent compound in corneal
epithelium.
a
2
-Agonist
a
2
-Agonist showed an IOP lowering effect and is
used for the treatment of glaucoma. Clonidine, a
representative selective a
2
-agonist, has been used
as an ocular hypertensive agent via topical
administration. However, it can also penetrate
to the central nervous system (CNS) through the
blood-brain barrier (BBB) due to its high lipo-
philicity and causes centrally mediated cardio-
vascular side effects.
89
Therefore, to reduce the
adverse effect, p-aminoclonidine (apraclonidine),
which possess higher polarity than clonidine, was
synthesized and is used for reducing the IOP. The
introduction of the p-amino group resulted in a
reduction of adverse effects, but also a decrease of
corneal permeability because of an increase in
polarity.
Brimonidine, a quinoxaline derivative, is more
lipophilic than apraclonidine but less lipophilic
than clonidine.
90
Conversion of 2,6-dicloro-p-
aminobenzene into 5-bromoquinoxaline provided
more than 20-fold higher corneal permeability
and 10-fold higher drug levels in aqueous humor
after instillation (Tab. 7). Although this drug
passes BBB, its side effects are tolerable.
91
This
may be due to less penetration to the CNS than
clonidine in addition to the receptor subtype
selectivity. On the other hand, to minimize access
the CNS without a loss of ocular penetration,
derivation of brimonidine has been reported.
Munk et al. synthesized brimonidine analogs that
possessed the 5-methyl group instead of the 5-
bromo group.
92
The methyl derivative AGN
Table 6. Physicochemical and Ocular Pharmacokinetic Properties of Propranolol and its Oxime Prodrug
88
Compound ACD log D
7
a
Concentration (mg/mL or g)
b
0.5 h 1 h
Propranolol
3.21
1.28 (AH
c
)
8.05 (ICB
d
)
0.26 (AH
c
)
0.00 (ICB
d
)
Propranolone oxime
3.27
0.86
e
(0.04
f
) (AH
c
)
9.90
e
(2.11
f
) (ICB
d
)
1.51
e
(0.71
f
) (AH
c
)
1.79
e
(1.79
f
) (ICB
d
)
a
Distribution coefcient in pH 7 was calculated using ACD/Labs software.
b
Drug concentration after instillation at 0.5 or 1 h.
c
Aqueous humor.
d
Iris-ciliary body.
e
Total concentration (prodrugpropranolol).
f
Propranolol concentration.
191103 and its corresponding benzodioxane deri-
vative AGN 192836 crossed the BBB, but the
structurally related benzoxazin derivative AGN
193080 did not. This benzoxazin derivative had
higher IOP lowering efcacy than clonidine. This
suggests that AGN 193080 shows good corneal
penetration with low BBB penetration. The
tetrahydroquinoxaline derivative AGN 192172
demonstrated neither IOP lowering efcacy nor
BBB penetration. These data indicated that the
introduction of morpholine ring may be useful for
decreasing BBB penetration without corneal
penetration.
Prostaglandin (PG) F
2a
Derivatives
Topical administration of PGF
2a
lowered the
elevated IOP of glaucoma patients.
89,93
Ocular
Table 7. Physicochemical and Ocular Pharmacokinetic Properties of a
2
Agonists
Compound log D
7.4
a
P
app
b
(10
6
cm/s) C
1h
(mg/mL or g)
c
(Aqueous Humor/Iris) Refs.
Chlonidine
0.52 36 11.53/13.87 90
Aprachlonidine
0.96 0.44 0.59/0.87 90
Brimonidine (AGN190432)
0.17 9.8 7.67/7.84 90
AGN 191103
3.40 91
AGN 192836
91
AGN 193080
0.80 92
AGN 192172
3.90 92
a
Distribution coefcient values in pH 7.4.
b
c
Drug concentration in aqueous humor at 1 h after instillation.
2474 SHIRASAKI
penetration of PGF
2a
is limited because it will
exhibit an ionized form in tears at neutral pH due
to the presence of the carboxylic acid function-
ality.
94
Esterication of the carboxyl moiety at
1-position signicantly increased the corneal
permeability and the IOP lowering activity
(Tab. 8).
9598
Since esters of PGF
2a
are metabo-
lized to the free acid in the cornea, they act as
prodrugs. Esterications of alcohol moiety at
11- and/or 15-position of PGF
2a
also provided
prodrugs, which showed an enhanced corneal
permeability.
98
However, 11,15-diester had lower
corneal permeability than 11- or 15-monoester.
Di-esterication may cause the decline of perme-
ability to the corneal epithelium and hydrophilic
stroma because it leads to an increase in
molecular weight and an excessive lipophilicity
causing strong interaction between the molecule
Table 8. Corneal Permeability and ACD log D
7
of PGF
2a
and Related Compounds
Compound
P
app
(10
6
cm/s)
a
ACD log D
7
b
Rabbit Human Porcine
PGF
2a
derivatives
PGF
2a
R
1
R
11
OH, R
15
OH 0.2
c
/0.13
d
1.7
e
0.13
f
0.09
R
1
R
11
OH, R
15
OCOCH
3
1.0
c

R
1
R
11
OH, R
15
OCOC(CH
3
)
3
5.2
c

R
1
OCH
3
, R
11
H, R
15
OH 8.9
g
2.70
PGF
2a
isopropyl ester (PGF
2a
) R
1
OCH(CH
3
)
2
, R
11
OH, R
15
OH 19
c
3.3
e
29
f
3.58
R
1
OCH
2
Ph, R
11
OH, R
15
OH 26
g
4.45
R
1
R
11
1,11-Lactone, R
15
OH 18
c
2.80
R
1
OH, R
11
COC(CH
3
)
3
, R
15
OH 7.7
e
2.27
R
1
OH R
11
R
15
OCOC(CH
3
)
3
4.0
c
2.6
e
4.33
S-1033 (15-deoxy PGF
2a
) R
1
R
11
R
15
OH 0.58
d
1.77
S-1033 methyl ester R
1
OCH
3
, R
11
R
15
OH 1.3
d
4.55
Isopropyl unoprostone R
1
OCH(CH
3
)
2
0.95
h
4.63
Unoprostone R
1
OH ND
h,i
0.97
a
b
Distribution coefcient was calculated using ACD/Labs software.
c
Ref. 97.
d
Ref. 102.
e
Ref. 98.
f
Ref. 96.
g
Ref. 95.
h
Ref. 104.
i
The drug was not detected in the receiver cell.
and membrane lipids of corneal epithelium. The
9-pivaloyl ester and 9,11-lactone of PGF
2a
were
unsuitable for prodrugs, because they were not
substantially hydrolyzed by ocular tissue homo-
genates.
99
S-1033, a 15-deoxy derivative of PGF
2a
, showed
higher permeability than PGF
2a
. Removal of the
polar hydroxyl group led to the increased perme-
ability. Additionally, esterication of the 1-car-
boxyl moiety resulted in a further increase in
corneal permeability (Tab. 8).
100
PGF
2a
1-ester analogs show high corneal
permeability and IOP-lowering activity, but are
not suitable for clinical use due to side effects such
as irritation and conjunctival hyperemia. There-
fore, to reduce the side effects, several v-side
chain (1320 position) analogs of PGF
2a
have been
synthesized. The addition of two carbons at the
20-position of a PGF
2a
metabolite (15-keto-13,14-
dihydro PGF
2a
) provided a compound (unopros-
tone) with an improved side-effect prole in the
eye and without a loss of IOP-lowering activ-
ity.
101103
Unoprostone is a carboxylic acid and
showed quite low corneal permeability (Tab. 8).
Therefore, its isopropyl ester (isopropyl unopros-
tone, UF-021) is marketed as an anti-glaucoma
agent.
104
Substitution of carbons at positions
1820 of PGF
2a
with phenyl or at positions
1720 with phenoxy moiety also improved the
side-effect prole.
105107
17-phenyl-18,19,20-tri-
nor PGF
2a
(17-Ph-PGF
2a
) and 16-(3-chlorophe-
noxy)-17,18,19,20-tetranor PGF
2a
(cloprostenol)
demonstrated a comparable corneal permeability
to PGF
2a
(Tab. 9).
108
The isopropyl ester of 17-Ph-
PGF
2a
(17-Ph-PGF
2a
-IE) exhibited lower corneal
permeability than the isopropyl ester of PGF
2a
(PGF
2a
-IE). Latanoprost, the 13,14-dyhydro
analog of 17-Ph-PGF
2a
-IE, showed improved
pharmacological proles and is widely used as
anti-glaucoma agent.
10
Amidation of 17-Ph-
PGF
2a
is also effective for increasing corneal
permeability, but showed lower impact on corneal
permeability than esterication.
109
This may be
because an amide group is a hydrogen bond
donor. Since the hydrolysis rate of amides is
generally slower than that of esters, amide
derivation is not suitable for prodrugs except for
nonsubstituted amide (CONH
2
), which showed a
somewhat higher hydrolysis rate than mono-
substituted amides (CONHR).
110
Bimatoprost,
an ethyl amide derivative of 17-Ph-PGF
2a
, is used
for the treatment of glaucoma and is most likely to
show an ocular hypotensive effect without meta-
bolism to the corresponding free acid.
109
Con-
version of the hydroxyl group at position 15 of
17-Ph-PGF
2a
-IE into a carbonyl group resulted in
an increase in corneal permeability. Since the con-
version did not signicantly change the lipophi-
licity, the reduction of the number of hydrogen
bond donor would enhance the permeability.
108
To enhance the corneal permeability of PGF
2a
and its analogs, esterication and amidation of
the C1-carboxyl functionality is the most desirable
derivation. Esterication of the alcohol moiety
can also increase the corneal permeability due to
an increase in lipophilicity and a reduction in the
number of hydrogen bond donors. All ocular
PGF
2a
analog prodrugs on the market (isopropyl
unoprostone, latanoprost and travoprost) are
isopropyl esters, which would show suitable stabi-
lity in aqueous solution due to its bulky structural
nature.
104,107,108
Because amide derivatives are
also generally stable for hydrolysis, they are sup-
erior to ester derivatives in the self-life.
Anti-Infective Agents
Fluoroquinolones
Fluoroquinolone is a class of anti-bacterial agents,
which are widely used for the treatment of ocular
infection as eye drops.
111115
Increasing the
lipophilicity of uoroquinolones has a tendency
to increase corneal penetration (Tab. 10). Robert-
son et al. reported that the corneal permeability of
seven uoroquinolones (which are used as
eye drops) is positively correlated with their
MardinDarby canine kidney (MDCK) cell perme-
ability.
112
Moxioxacin demonstrates the highest
ocular penetration in commercial products used as
eye drops.
112115
Antiviral Agents (Acyclovir/Ganciclovir)
The acyclic guanosine analogs acyclovir (ACV)
and ganciclovir (GCV) are clinically used in the
treatment of various infections caused by the
herpes family of viruses.
116,117
However, these
drugs have low ocular permeability due to their
hydrophilic nature and did not show sufcient
efcacy for intraocular infection via topical
instillation.
118,119
Therefore, the lipophilic pro-
drug approach of these drugs was investigated.
Esterication of ACV and GCV with fatty acids
has improved the corneal permeability (Tabs. 11
and 12).
120125
These esters are rapidly hydro-
lyzed to the parent drugs in the cornea. It is shown
that increasing the length of an alkyl side chain of
2476 SHIRASAKI
acyclovir ester prodrug from propionyl to hex-
anoyl leads to the gradually enhancement of
ocular penetration in vivo in addition to in vitro
corneal permeability.
126
The conversion of ACV and GCV into their L-
valine ester (valacyclovir
127
and valganciclovir,
128
respectively) or into dipeptide esters having
specic amino acid sequences remarkably
enhance the corneal permeability.
129,130
These
derivatives possess a free amino group and show
high aqueous solubility but low lipophilicity.
However, their corneal permeability is higher
than that expected from their lipophilicity. This
may arise from an active uptake by amino acid or
Table 9. Corneal Permeability and ACD log D
7
of 17-Ph PGF
2a
and Related Compounds
Compound
P
app
(10
6
cm/s)
a
ACD log D
7
b
Human Porcine
17-Ph PGF
2a
derivatives
17-Ph PGF
2a
(17-Ph-18,19,20-trinor PGF
2a
)
R
1
OH
0.696
c
0.10
Bimatoprost
R
1
NHC
2
H
5
3.24
d
1.98
R
1
OCH(CH
3
)
2
5.9
e
3.56
15-Keto-17-Ph PGF
2a
11.0
e
3.34
Latanoprost (13,14-dihydro-17-Ph PGF
2a
) 6.8
e
3.65
Cloprostenolol 1.49
c
0.09
a
b
Distribution coefcient was calculated using ACD/Labs software.
c
Ref. 98.
d
Ref. 110.
e
Ref. 108.
oligopeptide transporters in corneal epithelium
such as LAT 1, LAT 2, and PepT1.
131
Therefore,
such amino acid and dipeptide prodrug appro-
aches are useful for increasing ocular penetration.
The corneal permeability of these derivatives is
higher than that of aliphatic ester prodrugs. The
rank order of ocular penetration was Val-Gly >
Val >Tyr-Val >Val-Val in the case of acyclo-
vir amino acid or dipeptide esters.
132
In the case of
ganciclovir amino acid or dipeptide esters, the
rank order of ocular penetration was Val-Tyr >
Val-Val >Val >Gly-Val.
122
Table 10. Physicochemical and Ocular Pharmacokinetic Properties of Fluoroquinolone Derivatives
Compound Sol. (%)
a
P
app
(10
7
cm/s)
log D
7.4
AQC
max
(mg/mL)
d
AUC
01
(mg h/mL)
e
MDCK
b
Cornea
c
Ref. 115 Ref. 114 Ref. 113
Noroxacin
0.05 3.3 1.63 1.60
0.21,
0.92
0.22,
0.92

Ciprooxacin
0.02 4.5 2.46 1.52
0.64,
3.18

Lomeoxacin
0.13 6.6 3.58 1.45
1.25,
4.22

Ooxacin
0.35 15.1 6.78 0.45
1.15,
3.20
1.59,
5.08
0.87,
2.24
Gatioxacin
0.21 10.3 4.6 0.97
2.30,
5.90
1.26,
2.52
Moxioxacin
>6.43 35.2 15.8 0.23
5.42
f
,
7.34
f
a
Aqueous solubility.
b
MDCK cell permeability (Ref. 112).
c
Corneal permeability (Ref. 112).
d
Drug concentration in aqueous humor after three times topical dosing to rabbit at 15 min interval.
e
The area under the curves for 0 h to innity.
f
AQC
max
and AUC values of moxioxacin (0.5% solution) were normalized to 0.3% solution.
2478 SHIRASAKI
Anti-Inammatory Agents
Nonsteroidal Anti-Inammatory Drugs (NSAIDS)
Most of NSAIDS for eye drops have arisen from
oral NSAIDS such as diclofenac,
133
bromfenac,
134
urbiprofen,
135
pranoprofen,
136
and ketorolac
tromethamine.
137
Ocular penetration of these
drugs is not very high due to the incorporation
of a carboxyl functionality that will completely
ionize in tears at a neutral pH. In addition to these
NSAIDS adapted from oral drugs, nepafenac, the
NSAID used only for eye drops, was recently
approved by FDA in 2005. Nepafenac is nonsub-
stituted amide prodrug of amfenac,
138
which is
used as an oral drugs for the treatment of
rheumatoid in Japan, and was designed to
improve the corneal permeability and tissue
distribution prole.
139
Nepafenac showed about
4- to 30-fold higher corneal permeability than
conventional NSAIDS such as diclofenac, bromfe-
nac and ketorolac (Tab. 13).
140
The permeability
data of amfenac were not given, but amidation of
carboxylic acid in amfenac would result in at least
a 28-fold increase in permeability than the parent
drug, based on the estimation from permeability
of ketorolac and ACDlog D
7
value of ketorolac and
amfenac. Since nepafenac showed low aqueous
solubility, it was formulated as an aqueous
suspension. Its high permeability enables it to
deliver to posterior segment of the eye in addition
to the anterior segment. Moreover, its duration of
action is longer than that of diclofenac.
141
Con-
version of carboxylic acid into nonsubstituted
amide is useful for the enhancement of corneal
permeability, although it leads to a decrease in
aqueous solubility. Amides are most likely to be
Table 11. Physicochemical and Pharmacokinetic Properties of Ganciclovir Ester Derivatives
Compound
Solb
a
(mM)
log D
7.4
b
or
ACD log P
c
P
app
(10
6
cm/s)
d
C
max
(mM)
e,f
AUC
inf
(mMmin)
e,g
Refs.
Aliphatic fatty acid esters
R
H 15.7 1.55
b
3.8 119
R
COCH
3
15.2 1.08
b
4.9 119
R
COCH
2
CH
3
11.9 0.92
b
5.7 119
R
CO(CH
2
)
2
CH
3
8.4 0.30
b
7.7 119
R
CO(CH
2
)
3
CH
3
4.1 0.07
b
24 119
a-amino acid or dipeptide esters
R
H 3.4 2.07
c
4.1 201 42259 130,132
R
Val 92 1.28
c
32 647 82112 130,132
R
ValVal 82 0.73
c
31 943 301370 130,132
R
ValTyr 74 0.55
c
1458 536278 130,132
R
TyrVal 68 0.54
c
130
R
ValGly 63 1.95
c
130
R
GlyVal 66 1.95
c
109 34460 130,132
R
TyrGly 68 1.77
c
130
R
GlyTyr 74 1.78
c
130
a
Solubility in pH 4.2 phthalate buffer.
b
c
Partition coefcient was calculated using ACD/Labs software.
d
e
After 2 h of corneal infusion (0.43%, 200 mL) via topical well.
f
The maximum concentration of GCV in aqueous humor.
g
The area under the curve for 0 h to innity in aqueous humor.
hydrolyzed slower than ester and are metabolized
in iris-ciliary body and choroid/retina rather than
the cornea. However, in the case of a more
lipophilic NSAID such as urbiprofen, amidation
did not change the corneal permeability
(Tab. 13).
142
Steroids
Prednisolone and dexamethasone derivatives are
used for the treatment of ocular inammation.
Their acetyl and phosphate esters at the 21-
position of prednisolone are widely used as eye
drops. Both esters of prednisolone rapidly repro-
duced the parent drug in the cornea (Tab. 14). The
purpose of acetylation is to enhance the corneal
permeability, while the purpose of phosphoryla-
tion is to increase the aqueous solubility. The
corneal permeability of the acetate and phosphate
are 30-fold higher and 10-fold lower than that of
their parents, respectively.
143
Although the phos-
phorylation greatly decreased its corneal perme-
ability, the AUC
06h
values in aqueous humor
after instillation of phosphate 0.5% solution to
rabbits were approximately equal to that after
instillation of acetate 0.5% suspension possibly
due to the great increase in aqueous solubility.
144
Esterication of dexamethasone at the 21-
position with fatty acids also increases the corneal
permeability (Tab. 15).
145
Increasing the alkyl
chain from acetyl to butyryl gradually enhanced
the corneal permeability. The valeryl ester is
slightly resistant to hydrolysis, but its ux of
dexamethasone through the cornea is similar to
that of butyryl ester. The palmitoyl ester did not
permeate substantially to the cornea. Since the
lipophilicity of palmitoyl ester is too high (log
P12.4), it may be trapped in the corneal
membrane. The phosphate and m-sulfobenzoate
prodrugs of dexamethasone have been marketed
Table 12. Physicochemical and Pharmacokinetic Properties of Acyclovir Ester Derivatives
Compound
Solb
a
(mM)
log D
7.4
b
/
ACD log D
7
c
P
app
(10
6
cm/s)
d
C
25 min
e
or
C
max
f,g
(mM)
AUC
inf
f,h
(mMmin) Refs.
Aliphatic fatty acid esters
R
H 11.2 1.22
b
/1.76
c
3.7 38
e
118,126
R
COCH
2
CH
3
5.0 0.85
b
/0.57
c
4.3 118,126
R
CO(CH
2
)
2
CH
3
4.6 0.08
b
/0.04
c
5.1 42
e
118,126
R
COCH
2
CH(CH
3
)
2
4.8 0.06
b
/0.22
c
3.9 118,126
R
CO(CH
2
)
3
CH
3
1.5 0.30
b
/0.49
c
6.5 59
e
118,126
R
COC(CH
3
)
3
1.6 0.37
b
/0.13
c
118,126
R
CO(CH
2
)
4
CH
3
0.7 0.93
b
/1.02
c
8.5 79
e
118,126
a-amino acid or dipeptide esters
R
H >30 1.76
c
4.2 129
R
Val >30 1.71

c
12 124
g
7247 122,129
R
ValVal >30 1.52

c
9.9 34
g
2063 122,129
R
ValGly >30 2.27

c
12 200
g
12007 122,129
R
ValTyr >30 0.84

c
7.2 129
R
TyrVal >30 1.33

c
8.3 80
g
13930 122,129
a
Solubility in pH 7.4 phosphate buffer.
b
c
Distribution coefcient in pH 7 was calculated using ACD/Labs Software.
d
e
ACVconcentration in aqueous humor at 25 min after instillation of 50 mL of a 1 mMsolution. The data were constructed fromthe
graph in Ref. 126.
f
After 2 h of corneal infusion (200 mL) via topical well.
g
The maximum concentration of ACV in aqueous humor.
h
The area under the curve for 0 h to innity in aqueous humor.
2480 SHIRASAKI
as water-soluble derivatives. The corneal perme-
ability of phosphate and m-sulfobenzoate is about
1.3 and 10 times less, respectively, than that of the
parent. The 2.5 mM solution of the phosphate
partly penetrates into aqueous humor after
instillation. The AUC of the phosphate was
twofold less than that of the 2.5 mM dexametha-
sone suspension and threefold less than that of the
butyrate suspension. In contrast, the m-sulfo-
benzoate solution was not detectable in aqueous
humor probably due to its low corneal perme-
ability.
Table 13. Physicochemical and Pharmacokinetic Properties of NSAIDs
Compound ACD log D
7
a
Corneal permeability P
app
(10
6
cm/s) Refs.
Nepafenac
1.17 64 140
Amfenac
0.62
Bromfenac
0.30 3.4 140
Diclofenac
1.28 15 140
Ketorolac
0.60 2.3 140
Flurbiprofen
1.31 21 142
Flurbiprofen amide
3.06 22 142
a
Distribution coefcient in pH 7 was calculated using ACD/Labs Software.
Table 14. Ocular Pharmacokinetic Properties of Prednisolone Derivatives
143,144
Compound P
app
(10
6
cm/s)
a
C
max
(mg/mL)
b
AUC
06h
(mg h/mL)
c
Prednisolone
R
H
2.7
Prednisolone disodium phosphate
R
P(O)(ONa)
2
(1% solution)
0.26 1.5 (2.1)
d
3.7 (4.5)
d
Prednisolone acetate
R
COCH
3
(1% suspension)
83 1.6 4.2
a
b
Prednisolone concentration in aqueous humor after instillation of prednisolone prodrugs.
c
The area under the curve for 06 h in aqueous humor.
d
Total concentration (prodrugprednisolone).
Table 15. Physicochemical Ocular Pharmacokinetic Properties of Dexamethasone Derivatives
145
Compound log P
a
P
app
(10
6
cm/s)
b
C
max
(ng/mL)
c
AUC
03h
(ng h/mL)
d
Dexamethasone
R
H
2.12 5.1 75 104
Dexamethasone
disodium phosphate
R
P(O)ONa
2
0.54 3.9 39 54
Dexamethasone
sodium m-sulfobenzoate
R
1.65 0.51 <5 0

R
COCH
3
2.92 21
R
COCH
2
CH
3
3.19 29
R
CO(CH
2
)
2
CH
3
3.95 54 82 161
R
CO(CH
2
)
3
CH
3
4.70 15
R
CO(CH
2
)
14
CH
3
12.4 0 <5 0
a
Partition coefcient.
b
c
Dexamethasone alcohol concentration in aqueous humor after instillation of dexamethasone prodrugs.
d
The area under the curve for 03 h in aqueous humor.
2482 SHIRASAKI
Fatty acid esterication of steroids is extremely
effective for enhancing of corneal permeability.
Phosphorylation of steroids at the 21-position can
provide highly water-soluble prodrugs. Although
the phosphorylation led to a great decrease in the
corneal permeability, its drug penetration into
aqueous humor is similar or slightly lower than
the parent drug due to compensation by the
increased aqueous solubility. It is expected that
the increasing drug concentration in formulation
will produce large concentration gradients and
high ocular penetration. Esterication with m-
sulfobenzoic acid also resulted in an increase in
aqueous solubility, but its ocular penetration
would be reduced greatly because of a decrease
in corneal permeability.
Others
Calpain Inhibitor
Calpains, a family of cysteine endoproteases,
degrade lens proteins such as crystalline. There-
fore, calpain inhibitors are studied as a potential
anti-cataract agent.
146148
SJA6017, a dipeptidyl
aldehyde, shows very high potency against two
major calpain isoforms.
149
However, instillation
of SJA6017 aqueous suspension showed only low
concentration in aqueous humor (Tab. 16).
150
The low ocular penetration of SJA6017 may be
in part due to the presence of the reactive
aldehyde group, which may form reversible co-
valent adducts with nucleophiles in biomolecules.
Consequently, to investigate calpain inhibitors
that have the superior corneal permeability,
Nakamura et al.
150
modied the structure of
SJA6017 using two approaches. One approach
was to introduce into a pyridine ring as a water-
solubilizing group. Another is to convert the
reactive aldehyde moiety with hemiacetal moiety
that is a masked aldehyde with less reactivity.
Both approaches increased the ocular penetra-
tion. 3-Pyridlyacetomide analog (SNJ-1664) and
hemiacetal analog (SNJ-1709) of SJA6017 showed
a six- and eight-fold higher ocular penetration,
respectively, following instillation of their suspen-
sions than SJA6017. Furthermore, the conversion
of a (4-uorophenyl)sulfonamide moiety of SNJ-
1709 into a phenylthiourea moiety provided a
compound (SNJ-1715) with about 30-fold higher
increase of AUC in aqueous humor. SNJ-1709 and
SNJ-1715 have the similar aqueous solubility and
log P values, but have signicantly different
melting points (about 162 and 628C, respectively).
The superior ocular penetration of the thiourea
derivative is possibly due to the difference in
melting point. The low melting point may be
capable of enhancing corneal permeability
through an increase in the dissolution rate. A
good positive linear correlation between disso-
lution rate and oral bioavailability has been
reported.
151
It was also reported that transdermal
absorption of drugs correlated with their melting
points.
152
In the case of suspension formulation,
the difference in dissolution rate greatly affects
the ocular penetration because of the short con-
tact time between the drugs and the corneal
surface.
153
Moreover, Nakamura et al.
154
reported the
cyclic hemiacetal analogs (Tab. 16). A cyclic
hemiacetal SNJ-1757 in this series showed a
3.5-fold increase in corneal permeability in vitro
than did the corresponding linear aldehyde
(dehydroxy analog SNJ-1770). Both compounds
were evaluated for reactivity with semicarbazide
(H
2
NNHCONH
2
) hydrochloride, which simulates
biomolecules containing nucleophiles such as
the NH
2
and SH groups. The cyclic hemiacetal
SNJ-1757 did not signicantly react with semi-
carbazide, whereas the corresponding linear
aldehyde SNJ-1770 immediately reacted and
formed a semicarbazide adduct. These results
suggested that the presence of aldehyde moiety is
a limiting factor for corneal permeability.
Conversion of the aldehyde into the hemiacetal
provided an increase in corneal permeability,
which may be ascribed to a reduction of the
electrophilicity. A decline of electrophilicity by
structure modication or formation of prodrug
is desirable for enhancement of the corneal
permeability.
Quinidine
Quinidine is not an ocular drug, but has been
investigated for the corneal permeability as a
model P-gp substrate. Jain et al.
155
attempted
the transporter-targeted prodrug derivatization.
Esterication of the hydroxyl group of quinidine
with L-valine or L-valyl-L-valine showed a 1.5- and
3-fold increase in the corneal permeability com-
pared to quinidine (Tab. 17).
156
The corneal
permeation of quinidine is most likely to be
limited by efux, via P-gp on the corneal epi-
thelium. Attaching L-valine or L-valyl-L-valine to
quinidine not only signicantly decreases the
afnity to P-gp but also may increase the af-
nity to oligopeptide transporters. Such prodrug
approaches are useful for the improvement of
corneal permeability of P-gp substrates.
APPROACHES FOR MOLECULAR DESIGN TO
ENHANCE OCULAR PENETRATION
As mentioned above, to enhance the ocular
penetration of drugs, aqueous solubility and
corneal permeability can be important factors.
Approaches for molecular design to improve these
factors are described below. There are roughly two
classications of these approaches: the structure
modication of molecules themselves and the
prodrug approach. These strategies are summar-
ized in Table 18.
Structure Modication Approach
(Nonprodrug Approach)
Ophthalmic drug compounds require not only
high aqueous solubility but also adequate lipo-
philicity to penetrate to the membranes. Although
Table 16. Physicochemical and Ocular Pharmacokinetic Properties of Calpain Inhibitors
Compound
Solb
(mg/mL)
a
log D
7
b
P
app
(10
6
cm/s)
c
C
max
(mg/mL)
d
AUC
(mg h/mL)
e
Refs.
SJA6017
0.10 1.7 ND 0.037 0.051 150
SNJ-1664
>100 ND 0.21 0.31 150
SNJ-1709
1.5 0.60 ND 0.21 0.39 150
SNJ-1715
1.5 0.70 1.1 1.0 1.7 150
SNJ-1757
2.0 0.38 19 ND ND 154
SNJ-1770
0.91 0.54 5.4 ND ND 154
a
Solubility in pH 7 phosphate buffer.
b
Distribution coefcient in pH 7.
c
d
Aqueous humor concentration after instillation of 50 mL of 0.5% suspension.
e
The area under the curve for 03 h.
2484 SHIRASAKI
an introduction of strong ionizable centers, such
as phosphate, sulfonate, carboxylate and guani-
dino groups increases the aqueous solubility, it
will also simultaneously decrease the membrane
permeability because of the increase of the
charged form. In contrast, incorporation of lipo-
philic moieties to enhance the corneal perme-
ability led to a decline in the aqueous solubility.
Moreover, the excess lipophilicity would reduce
the unbound fraction in the target tissues and the
pharmacological activities. It is desirable that the
molecules for eye drops should be designed to have
high aqueous solubility without a loss of lipophi-
licity for absorption. These examples of molecular
design are summarized in Table 19.
An example of the molecular design is an
incorporation of heterocycles including more than
two heteroatoms, which generally show high
solubility for both aqueous solution and organic
solvent, and can be considered to be amphipathic
molecules (amphiphiles). Introduction of hetero-
cycles led to the ophthalmic drugs, such as
dorzolamide, timolol and brimonidine, having
excellent ocular pharmacokinetic properties.
Another approach is to introduce a nonionic
amphiphile like an oligoethylene glycol methyl
ether chain, which is able to enhance aqueous
solubility without a large loss of lipophilicity. In
the case of oral absorption, incorporation of such
functionality produced the highly oral bioavail-
able compounds.
157,158
Introduction of a basic
moiety like an amino or pyridine moiety as an
ionizable center is also useful for increasing
aqueous solubility. In this case, one problem is
the pK
a
value of the basic groups. The compounds
that extensively ionize around neutral pH may
decrease the corneal permeability. Since ampho-
lytes like uoroquinolones and dorzolamide would
exist as zwitterions, which is an apparent non-
ionic species, it is expected that the compounds
will show high aqueous solubility and the corneal
permeability to some extent.
Table 17. Partition Coefcient and Corneal Permeability of Quinidine and its Val and ValVal Derivatives
156
Compound log P
a
P
app
(10
6
cm/s)
b
None Verapamil
c
GlySar
d
Quinidine
R
H
19 71
ValQuinidine
R
Val
3.52 31 35 18
ValValQuinidine
R
ValVal
4.62 52 50 35
a
Partition coefcient.
b
c
Corneal permeability with verapamil (P-gp inhibitor).
d
Corneal permeability with Glycylsarcosine (oligopeptide transporter substrate).
Table 18. Summary of Strategies for Improvement of
Ocular Penetration
Structure modication (nonprodrug) approaches
Optimization of lipophilicity
Enhancement of aqueous solubility
Reduction of hydrogen bond donors
Reduction of molecular weight
Removal of highly reactive moieties
Decline in melting point
Prodrug approaches
Optimization of lipophilicity
Enhancement of aqueous solubility
Reduction of hydrogen bond donors
Enhancement of afnity for uptake transporters
In addition to lipophilicity, hydrogen-bond
ability also involves membrane permeability. A
decline in the number of hydrogen bond donors
can enhance the membrane permeability.
Removal of hydrogen bond donor is more effective
for improvement of membrane permeability than
introduction of additional hydrocarbon.
159
The
corneal permeability of the 15-keto-17-Ph PGF
2a
-
IE is twofold higher than 17-Ph PGF
2a
-IE (the
corresponding 15-alcohol analog; Tab. 9).
108
Removal of the 15-alcohol group of PGF
2a
also
provided about 10-fold increase in corneal perme-
ability.
102
In the case of b-blockers, the drugs with
hydrogen bond donors in the substituents showed
lower permeability than the drug without hydro-
gen bond donors (Tab. 4).
79
Additionally, it has
been reported that P-gp, an efux transporter,
recognize hydrogen bond donors. An increase in
Table 19. Examples of Structure Modication (Nonprodrug) Approaches for Improvement of Ocular Penetration
Strategy Approach and examples
Lipophilicity and aqueous solubility Incorporate heterocycles including more than two heteroatoms
Preferable log D
7.4
is about 23
Incorporate nonionic amphiphiles
Incorporate amino groups
Avoid strong ionizable centers
Hydrogen bonding Reduce hydrogen-bond donors
Molecular weight Reduce molecular weight MW<400
Melting point Lowered melting point (for suspensions)
Reactivity Avoid reactive moieties
2486 SHIRASAKI
number of hydrogen bond donors in molecules
may raise the possibility of substrate recognition
by efux transporters including P-gp. Therefore,
to enhance the corneal permeability, reduction of
number of hydrogen bond donor is important.
Small molecular weight tends to increase both
aqueous solubility and membrane permeability.
For instance, CNS drugs on the market, which
need to pass BBB that is a very tight barrier, have
smaller molecular weight than nonCNS drugs.
160
In ophthalmology, the P3 truncated calpain
inhibitors can pass the corneal membrane more
easily than calpain inhibitors having the P3
moiety (Tab. 16).
154
Small inhibitors will possess
both high aqueous solubility and corneal perme-
ability, possibly leading to a high ocular bioavail-
ability.
Reactive functionalities often limit the corneal
permeability. Of course, the functionalities that
form irreversible covalent adducts should be
avoided. Functionalities like aldehydes, which
can react with amino or thiol groups in biomole-
cules and produce the reversible covalent adduct,
and possibly reduce the corneal permeability.
154
Replacement of an aldehyde moiety with a
hemiacetal moiety, which is a masked aldehyde,
increases the corneal permeability possibly due to
decline of the electrophilicity in the molecule
(Tab. 16).
150,154
The lower reactivity would
diminish the reaction between the compound
and nucleophiles in membrane substances. Both
replacement of the reactive moieties with less or
nonreactive ones, and designing prodrugs with
their reactive sites masked are favorable for
enhancement of the corneal permeability.
In the case of suspension formulation, not only
aqueous solubility but also the dissolution rate
will affect ocular penetration. The rapid dissolu-
tion rate of the compound is preferable to
suspension formulations. A tentative index to
predict the dissolution rate is the meting point.
The thiourea calpain inhibitor with lower melting
point (MP 628C) demonstrated superior ocular
penetration to the sulfonamide derivative (MP
1628C).
150
Prodrug Approach
Prodrug design is a useful method to improve
physicochemical and pharmacokinetic properties.
Prodrugs are drugs with attached functionalities
in order to obtain favorable structural natures and
will regenerate their active parent form by
enzymatic or chemical reactions.
161
In ophthal-
mology, this approach is mainly used to improve
the corneal permeability and aqueous solubi-
lity.
17,162,163
Additionally, application for the
site-specic chemical delivery system (CDS) for
iris-ciliary targeting has also been investigated.
20
These prodrug approaches are capable of signi-
cantly improving the physicochemical properties
without a decreasing pharmacological activity.
However, the functional groups that can connect
the pro-moiety are limited to several groups, such
as hydroxyl, carboxyl and so on. These examples of
this approach are summarized in Table 20.
Prodrug derivatization is very effective for
enhancing not only the lipophilicity but also the
corneal permeability in circumstances where
incorporation of polar functionalities like a
carboxylic acid and an alcohol moiety lowered
the corneal permeability of the molecules. The
compounds including carboxylic functionalities
generally showed low corneal permeability due to
their ionization in tears at a neutral pH. Ester
derivatization of carboxylic acids can increase
lipophilicity and lead to the signicantly improved
corneal permeability. Since the cornea has high
esterase activity, eater prodrugs can easily
regenerate the parent drugs.
17
The major pro-
blems of ester prodrug derivatization are that
ester prodrugs would show decreased aqueous
solubility and increased susceptibility for hydro-
lysis. Considering their stability in an aqueous
solution, the bulky esters are desirable for pro-
moieties. For instance, all marketed ophthalmic
PGF
2a
prodrugs are bulky isopropyl
esters.
104,107,108
However, more bulky tert-butyl
esters are inadequate for pro-moieties because
they resist enzymatic hydrolysis.
164,165
Conver-
sion of carboxylic acids into amides is also effective
for improving the corneal permeability, but its
effect is less than that of esters (Tab. 9). Although
the nonsubstituted amides are partly hydrolyzed
by ocular tissues (Tab. 13),
140
the reactions of
mono-substituted amides are generally slower
and di-substituted amides are not substantially
hydrolyzed.
109
Thus, mono- and di-substituted
amides are not suitable for a pro-moiety.
The presence of hydrogen bond donors like an
alcohol or a phenol group causes low corneal
permeability. The conversion of them into fatty
acid esters increases the corneal permeability
(Tabs. 5, 8, 11, 12, 14 and 15). Taking into
consideration their stability in an aqueous solu-
tion, pivaloyl esters are favorable as pro-moiety.
The dipivaloyl ester of epinephrine is marketed as
the ophthalmic solution for the treatment of
glaucoma.
62
Ester prodrug derivatization is also
used in steroid drugs. In the case of compounds
having multiple alcohol functionalities such as
prostaglandins, each ester prodrugs having pro-
moiety at various positions should be compared,
because the impact on corneal permeability
depends on the position of esterication. The
permeability of multiple esters of a compound
with more than two alcohol groups is not always
higher than that of monoesters (Tab. 8).
Replacement of alcohol moiety by ketone leads
to an increase in corneal permeability through a
decline in the number of the hydrogen bond
donors. Since ketones are most likely to regener-
ate alcohols by ketone reductase in the corneal
epithelium and the iris-ciliary body,
20
ketones can
often be a pro-moiety. Furthermore, conversion of
ketones into oximes or methyloximes provides the
prodrug with increased stability in an aqueous
solution and sustained release of the parent
compound, because the oximes and methoximes
are generally more chemically and enzymatically
stable than the corresponding ketones. Since the
oximes and methoximes are hydrolyzed to the
corresponding ketones by enzymes that exist in
the iris-ciliary body, these can be considered as
site-specic enzyme activated delivery systems.
The several oximes or methoximes analogs of b-
blocking agents showed a higher and more
sustainable IOP reducing effect than the parent
compounds (Tab. 6).
20
These compounds did not
induce the transient bradycardia, a major side
effect of b-blockers, due to their nonactivation in
plasma.
On the other hand, the introduction of a strong
ionic moiety like a phosphate as pro-moiety easily
enhances aqueous solubility. Phosphate and m-
sulfobenzoate ester prodrug approaches are use-
ful to improve the aqueous solubility. Although
Table 20. Examples of Prodrug Approaches for Improvement of Ocular Penetration
Strategy Approach and examples
Lipophilicity Convert carboxylic acid into ester
Convert carboxylic acid into amide (slow hydrolysis)
Convert alcohol into ester fatty acid esters
Aqueous solubility Convert alcohol to phosphoric or m-sulfobenzoic acid ester
Hydrogen bonding Convert alcohol into ketone
Transporter Convert alcohol to a-amino acid or di-peptidyl esters (transporter-mediated)
Others Convert alcohol into oxime or methoximes via ketone (slow hydrolysis)
2488 SHIRASAKI
such strong ionic moieties signicantly increase
the aqueous solubility, they decrease corneal
permeability. Therefore, these approaches may
be benecial for lipophilic parent drugs like
steroids (Tabs. 14 and 15). In this case, the
increased solubility may decrease the corneal
permeability. The phosphate prodrug of predni-
solone shows approximately equal ocular pene-
tration after instillation to the corresponding
acetate ester, even though the phosphate had a
320-fold lower corneal permeability than the
acetate.
Conversion of a hydroxyl group into a specic a-
amino acid ester or a dipeptide ester with a
specic sequence results in enhanced corneal
permeability most likely due to transportation by
amino acid transporters (such as LAT 1 and 2) or
oligopeptide transporters (such as PepT1) in
corneal epithelium. Incorporation of a free amino
group also contributes to the increased ocular
penetration through an increase in aqueous
solubility. The compounds with (1) a specic a-
amino acid ester or (2) dipeptide esters with a
specic sequence recognized as a substrate by
uptake transporters, both showed higher ocular
penetration than that expected by their lipophi-
licity (Tabs. 11 and 12). This is a very effective
approach for enhancement of ocular penetration,
but the use will be limited by the parent compound
structure, its molecular weight, and physicochem-
ical properties.
So far, ester and amide prodrugs have been
reported as marketed eye drops. Since the linkage
between pro-moiety and the parent drug is most
likely to be chemically labile, the stability of the
formulation is often problematic.
CONCLUSION
As the many previous reports mentioned, a
balance between lipophilicity and hydrophilicity
is the most important factor for ocular penetra-
tion. The compounds for ophthalmic solution are
required a higher aqueous solubility than oral
drugs. The amphipathic structure incorporating
heterocycles or nonionic amphiphiles would be
favorable for the enhancement of ocular penetra-
tion due to addition of an appropriate lipophilicity
and hydrophilicity. Prodrug approaches for car-
boxylic acids and alcohols are also useful for the
enhancement in corneal permeability. In this
case, we should pay attention to the decline in
aqueous solubility and stability in an aqueous
solution. In the case of formulating the compounds
as an aqueous suspension, a compound having a
lower melting point is preferable. P-gp substrates
should be avoided to enhance corneal permeabil-
ity. On the other hand, the substrates of uptake
transporters may demonstrate high permeability.
Thus, in an ophthalmic drug, the molecular design
considering pharmacokinetic properties can pro-
vide more effective and less adverse drugs.
Moreover, such physicochemical property-based
drug design may be able to provide ocular drugs
that can reach the posterior segment of the eye via
topical instillation, in addition to the anterior
segment.
FUTURE DIRECTIONS
Currently, the conformation and pharmacophore
of many transporters and metabolic enzymes are
not fully understood. In future studies, the
understanding of crystal structure and the site
of binding for compounds will be developed and
will result in the capability of designing molecules
with good pharmacokinetic properties by in silico
screening. I expect that further development in
the eld of ocular pharmacokinetics and an
understanding of transporters and metabolic
enzymes will produce excellent drugs in the near
feature.
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Molecular Design for Enhancement of Ocular Penetration

N 2.06 (pH 7.2) 0.024 (pH 7.4) 61,66

N 1.11 7.92 (pH 7.65) 2.67/2.21 (AH

N 2.45 0.058 (pH 7.4) 3.91/4.45 (AH

CH 1.28 1.16/1.44 (AH

CH 1.28 3.05/2.76 (AH

OH 0.35 12.5 (pH 7.4) 8.1 (ICB

H 0.04 8.1 7.7

H 0.27 2.7 3.1

Val >30 1.71

ValVal >30 1.52

ValGly >30 2.27

ValTyr >30 0.84

TyrVal >30 1.33

1.65 0.51 <5 0

-dependent cationic and neutral amino acid

-independent large neutral amino

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