Download Advances and Challenges in Topical Ocular Medications

THERAPEUTICS UPDATE
Advances and
Challenges in Topical
Ocular Medications
Excipients can alter the tolerability of drops, which is a particularly
important factor in their long-term use.
BY JESSE T. MCCANN, MD, P H D
opical eye drops are the mainstay of ocular
pharmacology for the treatment of anterior
segment conditions. Because of their ubiquity
in ophthalmology, eye care specialists are
familiar with their pharmacologic classes and side
effect profiles, but they often underestimate the complexity of eye drops. Today’s topical medications are
complex drug delivery systems, and their efficacy and
the dose of drug that reaches its target structure can
depend greatly on the excipients contained in the
drop’s formulation. Although these materials are often
viewed and labeled as inactive ingredients, in many
cases, they can have as significant an effect on the
proper dosage and associated side effects as the active
drug itself. Furthermore, the excipients and methods
of formulation often vary among drops supplied by
different manufacturers.
The excipients can also alter the tolerability of
drops. Drugs used to treat chronic conditions such as
glaucoma are often used for an extended period of
time, and side effects associated with long-term use
limit the medications’ efficacy, utility, and tolerability.
T
TOPIC AL O CUL AR DRUG DELIVERY
Eye drops are a solution or suspension consisting of
water, the drug, excipients, and preservatives (Table 1).
Excipients are used to solubilize the lipophilic drug,
and stabilizers maintain the solution’s or suspension’s
consistency by preventing its settlement (in the case of
a suspension) or precipitation (in the case of a solution). The excipients can also include rheological modifiers such as hydrophilic polymers that make the drop
more viscous. A preservative is often included in multidose vials of eye drops to prevent bacterial coloniza-
tion. The pH of the formulation is accomplished using
ionic buffers, and most drops are formulated with a
pH of between 6.5 and 8.5.
When instilled in the eye, the average size of a drop
is about 50 mL. The maximum preocular retention
capacity of the eye is approximately 30 mL, so about
two-fifths of the eye drop is lost immediately upon
dosing. Thanks to the natural lacrimal drainage apparatus, the turnover rate of the deposited solution is
close to 1 mL per minute. Viscous additives can extend
how long the drug is present for absorption into the
TABLE 1. EXCIPIENTS COMMONLY USED
IN EYE DROP FORMULATIONS
Viscogens
• Carboxymethylcellulose
• Glycerin
• Polyvinylpyrrolidone
• Polyethylene glycol
Stabilizers
• Pluronic (triblock copolymers)
• Cyclodextrins
Preservatives
• Benzalkonium chloride
• ETDA
• SofZia (boric acid, propylene glycol, sorbitol, and zinc
chloride; Alcon Laboratories, Inc.)
• Purite (stabilized oxychloro complex; Allergan, Inc.)
SUMMER 2011 I GLAUCOMA TODAY I 57
THERAPEUTICS UPDATE
Figure 1. Stabilizing drugs with block copolymer surfactants
is common among drop formulations. The block copolymers
form micelles in a similar way to phospholipids. These
micelles have a hydrophobic core and a hydrophilic sheath,
allowing for the effective delivery of lipophilic materials in an
aqueous medium.
cornea and conjunctiva. Competition between ocular
and systemic absorption of the drug can limit its concentration in the anterior segment. Viscous polymer
additives can improve the drop’s spread and adhesion
by interacting with the eye’s mucosal layer. There is an
upper limit to patients’ tolerance of viscous eye drops,
however, as they can cause blurred vision, reflex blinking, and resistance to the eyelid’s movements. Several
commercial formulations use other methods to interact with the mucosal component of tears to increase
the effective retention time.1
Intraocular drug delivery to the anterior segment is
accomplished through corneal absorption. Tight junctions in the apical cells of the corneal epithelium are
the major barrier to a drug’s absorption. Lipophilic
drugs partition rapidly into the corneal epithelium,
which is also lipophilic, and then partition slowly
across the hydrophilic corneal stroma and into the
anterior chamber. Due to the multiphased nature of
corneal drug absorption, a parabolic relationship exists
between lipophilicity and maximum corneal absorption.2 Generally, the maximum corneal absorption
occurs with compounds that are 100 to 1,000 times
more soluble in oil than water. Therefore, to get an
aqueous eye drop that has sufficient potency, it is
often necessary to formulate a heterogeneous suspension of oily drug in an aqueous base (Figure 1).
Suspensions are complicated, and settling, flocculation, dose-to-dose reliability, particle size, and wetting
are all variable. Shelf life is an important factor in eye
Figure 2. A gamma-cyclodextrin molecule has a hydrophilic exterior and hydrophobic core. When mixed with a pharmaceutical, the cyclodextrin envelops the hydrophobic components of the drug molecule in a “bucket,” thereby increasing stromal
permeability.
58 I GLAUCOMA TODAY I SUMMER 2011
THERAPEUTICS UPDATE
“Many of the excipients in and
formulation processes for eye drops
are closely guarded secrets.
Excipients affect the shelf life of
many formulations.”
drop formulation, as drug degradation and leaching of
therapeutics into the polymeric matrix of the bottle
must be considered.
Many of the excipients in and formulation processes
for eye drops are closely guarded trade secrets.
Excipients affect the shelf life of many formulations. In
developing countries, for example, the quality of eye
drops is quite variable. One alarming example comes
from a recent study in the British Journal of Ophthalmology that showed that generic ciprofloxacin purchased in India varied in concentration between 33%
and 50%, and some levels were subtherapeutic.3
ADDITIVE S
Preservatives have been an important component of
eye drops since the 1950s, when multiple cases of
pseudomonal infections were traced to contaminated
eye drops. The current standard is benzalkonium chloride (BAK), a quaternary ammonium surfactant that
prevents bacterial growth by interrupting the formation of bacterial cell walls. Recently, BAK has been
shown to be allergenic for approximately 5% to 8% of
patients. Alcon Laboratories, Inc., developed the SofZia
system, a boric acid-based ionic buffer, in order to eliminate BAK from its travoprost formulation (Travatan Z).
BAK has been shown to increase corneal permeability by the same surfactant mechanism that increases
the absorption of a drug. Allergan, Inc., recently
released Lumigan (bimatoprost) 0.01% with comparable IOP-lowering efficacy to Lumigan 0.03%.4 Patients
using Lumigan 0.01% reported a lower rate of adverse
effects than those using the 0.03% formulation and
had a lower rate of discontinuation of the drop. The
lower concentration of the prostaglandin in the new
formulation is countered by a higher concentration of
BAK to increase corneal permeability and the amount
of prostaglandin delivered to the target tissues. It is
important to note that many of the adverse effects
reported for Lumigan were lower in the 0.01% formulation than the 0.03% formulation, indicating that
these effects might be due to an improper distribution
of the prostaglandin in the eye and not the
preservative.4
Advanced polymers and surfactant additives have
been shown not only to improve formulations’ stability but also drug delivery.5 The cyclodextrin family of
compounds is made up of a series of sugar molecules
bound together in a ring-shaped configuration. These
compounds have a hydrophilic exterior and a lesshydrophilic core (Figure 2), which allows for the inclusion and solubilization of more hydrophobic molecules in their core. Cyclodextrins were found to
improve the corneal permeability of multiple small
molecules and to enhance drug delivery to the anterior segment.6 Eye drop formulations, including
cyclodextrins, have also been found to have a longer
shelf life than traditional formulations without
cyclodextrins.6
CONCLUSI ON
The development of new therapeutic regimens for
topical ocular drug delivery has reached a turning
point. The discovery and testing of new drugs will
always remain important, but the development of
improved formulations will likely widen the range of
therapeutic options for diseases such as glaucoma.
Differences in formulation and excipient contents are
often trade secrets. Because differences in excipients
can result in the variability of formulations, eye care
specialists must carefully examine new generic agents
as they become available. ❏
This article is reprinted with permission from the
March 2011 issue of Advanced Ocular Care.
Jesse T. McCann, MD, PhD, is currently in
medical school at the Albert Einstein College
of Medicine, where he will graduate with
Alpha Omega Alpha honors in 2011. In 2012,
he will start as a resident in ophthalmology at
New York University Medical Center. Dr. McCann stated
that he receives no research support and has no competing interests. Dr. McCann may be reached at (646) 5718101; [email protected].
1. Urtti A.Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Delivery
Rev. 2006;58:1131-1135.
2. Davies NM.Biopharmaceutical considerations in topical ocular drug delivery. Clin Exp Pharmacol
Physiol. 2000;27:558-562.
3. Weir RE.Variability in the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol.
2005;89:1094-1096.
4. Katz LJ,Cohen JS,Batoosingh AL,Felix C,Shu V,Schiffman RM.Twelve-month,randomized,controlled trial of bimatoprost 0.01%,0.0125%,and 0.03% in patients with glaucoma or ocular hypertension. Am J Ophthalmol.2010;149(4):661-671.
5. Le Bourlais C,Acar L,Zia H,et al.Ophthalmic drug delivery systems—recent advances. Prog Retin
Eye Res.1998;17(1):33-58.
6. Sigudsson HH,Stefansson E,Gudmondsdottir E,et al.Cyclodextrin formulation of dorzolamide and
its distribution in the eye after topical administration. J Control Release.2005;102:255-262.
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