Download OCULAR DRUG DELIVERY: TARGETING THE POSTERIOR

Many efforts are under way to improve drug delivery to the back of the eye.
BY ARON SHAPIRO
One inch or less. That is the short distance an
ocular drug must travel to reach a target site at
the back of the eye. Research has come a long
way over the past 4 decades in efforts to make
this inch-long journey more successful.
Delivering ocular drugs to their target
tissues often requires them to traverse the
fat-water-fat structure of the corneal barrier
while ensuring minimum wastage through tear washout and
systemic absorption. This is why delivering drugs effectively to
the posterior of the eye is a challenge that many companies
have aimed to overcome. This installment of the Innovations in
Retina column describes recent developments in methods of
ophthalmic drug delivery to the posterior segment of the eye.
ROUTES OF DELIVERY
Topical, systemic, and intraocular delivery are the three
main routes through which ophthalmic medications are
administered to the back of the eye.
The easiest of these methods is topical application of
ophthalmic preparations in the form of solutions, suspensions, ointments, gels, or emulsions. Unfortunately,
only about 5% of the applied dose may enter the internal
structures of the eye, either through the cornea—which
is ideal for small lipophilic drugs—or through the conjunctiva and sclera, a route that is better suited for large,
hydrophilic drugs.
Most of the dose that is not washed out is systemically
absorbed through the conjunctiva and nasal fluids and also
through lacrimal drainage, pharynx, gastrointestinal tract,
skin, aqueous humor, and inner ocular tissues, ultimately to
be eliminated by metabolic processes.1
For effective systemic delivery, a relatively high drug
concentration must circulate in the plasma to achieve a
therapeutic dose within the eye. Oral drugs can be suitable
for posterior segment treatment, although their use exposes
the whole body to the drug, often giving rise to undesired
side effects.2
AT A GLANCE
• The risks and inconveniences of particular drug
delivery methods have encouraged industry to
create innovative routes of delivery.
• Delivery methods that rely on nanoparticles or
ocular inserts may provide better penetration to
the target site.
• Rather than use new drugs, some future delivery
systems will likely administer drugs retina
specialists use today.
In order to ensure that the required dose of a drug reaches
its target tissues, it may have to be administered by subconjunctival injection, intravitreal injection, or sub-Tenon
injection. Besides being invasive and carrying a degree of
risk of infection, these routes require multiple visits to the
doctor’s office and can greatly inconvenience patients.3
Patient-centered research has called for improved and
easier methods of drug delivery. Several strategies have
been proposed.
ENHANCING DELIVERY
Refining ocular drug delivery calls for different approaches
based on the target area and treatment requirements of
the disease to be treated. One practical approach involves
increasing the solubility and penetration capacity of a
drug; molecules with low aqueous solubility can be made
more water-soluble by the addition of hydrotropic solubility enhancers to the formulation, thus increasing the
bioavailability of the active ingredient. A drug formulation
containing penetration enhancers such as gelucires and
cyclodextrine microparticles can improve drug partitioning
into the corneal epithelium, thus allowing better penetration
JANUARY/FEBRUARY 2016 | RETINA TODAY 25
INNOVATIONS IN RETINA
OCULAR DRUG DELIVERY:
TARGETING THE
POSTERIOR SEGMENT
INNOVATIONS IN RETINA
of the drug through the cornea for more efficient delivery to
the posterior segment of the eye.1
Designing a drug that stays in contact with ocular tissues
for a longer time could ensure less precorneal loss and better penetration to the target site. There are several ways of
increasing the retention time of a drug. Viscosity-enhancing
polymers—such as derivatives of cellulose, polyvinyl alcohol,
polyvinyl pyrrolidone, carbomers, and hyaluronic acid and
its modified forms—absorb water to form viscoelastic gels
that are suitable vehicles for drug delivery.4,5 Liquid formulations that transition to gels upon instillation, called in situ
gelling systems, are typically triggered by changes in temperature, pH, or electrolyte interaction. Some compounds
or polymers have mucoadhesive properties that can increase
the residence time of a drug due to interaction between the
formulation and the mucus-covered ocular surface. Here,
the residence time is governed by the slower turnover of
mucus rather than the rapid turnover of the aqueous tear
component.4
Nanoparticles, which are sub–micron-sized particles
ranging from 10 nm to 1000 nm, can provide versatile drug
delivery systems. Drugs can be loaded into these particles
by attachment to the matrix, or the drug can be dissolved, encapsulated, or entrapped within their structures.6
Recently, sub–micron-sized liposomes have shown potential
as topical drug delivery systems in the form of eye drops for
the treatment of posterior segment diseases.1
Another strategy involves the use of drug-loaded devices
placed in the upper or lower conjunctival cul-de-sac or
even directly on the cornea. Such ocular inserts, whether
formulated to be removable or biodegradable, can function as controlled-release drug reservoirs. Contact lenses
have also been used for ocular drug delivery, and their
drug-loading capacity can be enhanced by the inclusion of
so-called container molecules that can accommodate the
molecules in their cavities.1
One way of overcoming all external barriers involves the
use of ocular implants, designed either to penetrate ocular membranes or to reside entirely within the eye. These
can be formulated to provide short-term medication or
to deliver medication for several years for chronic ocular
conditions.
SUSTAINED-RELEASE PRODUCTS
Four decades of research have resulted in the availability
of only four intraocular sustained-release drug delivery products with regulatory approval either globally or in Europe.
They include the fluocinolone acetonide intraocular implant
0.59 mg (Retisert, Bausch + Lomb), indicated for chronic
noninfectious posterior uveitis; the dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) for macular edema
secondary to branch or central retinal vein occlusion (RVO),
diabetic macular edema (DME), and posterior uveitis; the
26 RETINA TODAY | JANUARY/FEBRUARY 2016
“
Nanoparticles, which are
sub–micron-sized particles
ranging from 10 nm to
1000 nm, can provide versatile
drug delivery systems.
fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien,
Alimera Sciences), which uses pSivida’s Durasert technology
for delivery in patients with DME who have been previously
treated with corticosteroids without intraocular pressure
(IOP) elevation; and the ganciclovir intravitreal implant 4.5 mg
(Vitrasert, Bausch + Lomb) for cytomegalovirus retinitis.
Numerous innovative ocular drug delivery products are
now in development. Several sustained-release formulations of dexamethasone are in clinical development. A
dexamethasone depot (Dextenza, Ocular Therapeutix) is
undergoing phase 3 clinical evaluation for treatment of
postoperative inflammation and pain.7 The sustained-release
dexamethasone formulation EGP-437 (EyeGate) is delivered
noninvasively by the EyeGate II Delivery System for treatment of noninfectious anterior uveitis and macular edema.
In a phase 1/2 clinical trial, positive responses were seen
with EGP-437 compared with dexamethasone intravitreal
implant 0.7 mg control in patients with macula edema, and
dosing evaluation studies are continuing.8 Taiwan Liposome
Company is developing another sustained-release dexamethasone treatment (ProDex), delivered by the company’s
BioSeizer platform; this implant is in phase 2 studies for
macular edema.9
Sustained-release formulations of prostaglandin analogs
are also in development for the treatment of glaucoma
or ocular hypertension. In a phase 2 study, a travoprost
depot (OTX-TP, Ocular Therapeutix) showed average IOP
reduction over 3 months similar to that induced by topical
travoprost.10 In a separate phase 2 study, ENV515 (travoprost XR, Envisia) demonstrated statistically significant and
clinically meaningful reduction in IOP with results comparable to topical once-daily travoprost ophthalmic solution
(Travatan Z, Alcon).11
These same anterior segment delivery systems may
also be used intravitreally for treatment of posterior segment conditions, according to the companies. Ocular
Therapeutix is also developing a 6-month sustained-release
anti-VEGF hydrogel injection for retinal diseases such as
age-related macular degeneration, RVO, and DME. Such an
FUTURE DELIVERY SYSTEMS
Studies are under way to develop improved drug delivery
systems for various ocular conditions. Retinal therapies usually involve significant challenges for effective drug delivery,
and recent studies are attempting to address these concerns.
Evolving novel delivery systems include cell-penetrating
peptide constructs that can be fused to a therapeutic
protein transduction domain to transport microgram-size
quantities of large-molecule monoclonal VEGF inhibitors in a
topical eyedrop that penetrates to the posterior segment.
Slow-release depots of VEGF inhibitors are another area
of study. In vitro pharmacokinetic work is being done
on controlled-release polymer reservoirs of ranibizumab
(Lucentis, Genentech). A noninvasive electroosmotic
method of delivery of bevacizumab (Avastin, Genentech)
was shown to be successful and analogous to the efficacy
of intravitreal bevacizumab. A polymer nanoparticle system
with conjugation of bevacizumab was shown to reduce
leakage of the drug into the bloodstream and to prolong
its retention in the vitreous, making it potentially safer and
more effective than intravitreal injection. In vitro and in vivo
pharmacokinetics in rabbits of solid-state microparticles of
bevacizumab within sustained-release hydrogel matrices are
also being investigated.19
Steroid therapy is still very useful for retinopathy. A
dexamethasone intravitreal implant 0.7 mg together with
macular grid laser was found effective for treatment of RVO,
allowing the lengthening of time between injections. The
proprietary PRINT technology (Envisia) was used to create biodegradable implants and microparticle suspensions
of steroids for 6-month slow-release depots for intravitreal
delivery. Release kinetics of loteprednol in a nanoparticle gel
are being studied. Topical dexamethasone g-cyclodextrin
nanoparticle eyedrops were found to improve visual acuity
and decrease macular thickness in patients with DME.19
CONCLUSION
This article described just a few promising studies from
among the plethora being conducted in the realm of
sustained-release and alternative delivery methods for posterior segment drugs. Although it may be some time before
many or any of these technologies are available, this review
may provide a sense of hope, to know that so much change
is taking place in the field of ocular drug delivery. n
1. Morrison PW, Khutoryanskiy VV. Advances in ophthalmic drug delivery. Ther Deliv. 2014;5(12):1297-315.
2. Washington N, Washington WC, Wilson CG. Physiological Pharmaceutics: Barriers in Drug Absorption. CRC Press:
Boca Raton, Florida; 2001.
3. Yasukawa T, Tabata Y, Kimura H, Ogura Y. Recent advances in intraocular drug delivery systems. Recent Pat Drug
Deliv Formul. 2011;5(1):1-10.
4. Kaur IP, Smitha R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery.
Drug Dev Ind Pharm. 2002;28(4):353-369.
5. Shahwal V. Ocular drug delivery: an overview. International Journal of Biomedical and Advance Research.
2011;2(5):167-187.
6. Nagarwal RC, Kant S, Singh PN, Maiti P, Pandit JK. Polymeric nanoparticulate system: a potential approach for ocular
drug delivery. J Control Release. 2009;136(1):2-13.
7. Ocular Therapeutix. Product Candidates: Dextenza. www.ocutx.com/pipeline/dexamethasone-punctum-plug.
Accessed December 28, 2015.
8. EyeGate announces interim data from phase 1b/2a clinical trial of iontophoretic EGP-437 ophthalmic solution in
macular edema patients [press release]. EyeGate Pharma. November 5, 2015. www.eyegatepharma.com/uncategorized/eyegate-announces-interim-data-from-phase-1b-2a-clinical-trial-of-iontophoretic-egp-437-ophthalmicsolution-in-macular-edema-patients. Accessed December 28, 2015.
9. Taiwan Liposome Company. Pipeline: ProDex. www.tlcbio.com/en-global/pipeline/200. Accessed December 28,
2015.
10. Ocular Therapeutix. Product Candidates: Sustained Release Travopost. www.ocutx.com/pipeline/travoprostpunctum-plug. Accessed December 28, 2015.
11. Envisia Therapeutics’ lead product candidate, env515 (Travoprost XR), achieves primary efficacy endpoint in
phase 2a glaucoma clinical trial [press release]. Envisia Therapeutics. October 6, 2015. www.envisiatherapeutics.
com/envisia-therapeutics-lead-product-candidate-env515-travoprost-xr-achieves-primary-efficacy-endpoint-inphase-2a-glaucoma-clinical-trial. Accessed December 28, 2015.
12. Ocular Therapeutix. Product Candidates: Posterior Segment Injections. www.ocutx.com/pipeline/posteriorsegment-sustained-release-injections. Accessed December 29, 2015.
13. EyeGate Pharma. Technology: Eyegate II Delivery System. www.eyegatepharma.com/technology/eyegate-iidelivery-system. Accessed December 29, 2015.
14. Taiwan Liposome Company. Technology: BioSeizer. www.tlcbio.com/en-global/Page/bioSeizer-lipidbasedbiotherapeutics-smallmolecule-Sustained-release-TLC599-TLC198-prodex. Accessed December 29, 2015.
15. Oculis. Pipeline. oculispharma.com/pipeline. Accessed December 29, 2015.
16. Gudmundsdottir BS, Petursdottir D, Asgrimsdottir GM, et al. g-cyclodextrin nanoparticle eye drops with dorzolamide: effect on intraocular pressure in man. J Ocul Pharmacol Ther. 2014;30(1):35-41.
17. Replenish Inc. Our Technology: Ophthalmic Micropump System. www.replenishinc.com/our-technology/
ophthalmic-micropump-system. Accessed December 29, 2015.
18. pSivida Corp. Products: Durasert. www.psivida.com/products-durasert.html. Accessed December 29, 2015.
19. 2015 ARVO finds connections in innovative drug delivery, therapies. Ophthalmology Times. July 15, 2015.
Aron Shapiro
n
vice president of retina at Ora in A
ndover, Mass.
JANUARY/FEBRUARY 2016 | RETINA TODAY 27
INNOVATIONS IN RETINA
implant could significantly reduce the dosing frequency for
anti-VEGF therapies and the likelihood of side effects associated with monthly intravitreal injections.12
Two advanced delivery systems mentioned in this article
can now deliver sufficient doses of drugs to the retina over
prolonged periods. The EyeGate II Delivery System uses a
low-level electrical current to deliver a specified amount
of drug for each treatment. This noninvasive method,
powered by iontophoresis, can transfer high drug concentrations across ocular tissues to the posterior segment.13 The
BioSeizer platform is a lipid-based technology that can carry
a therapeutic agent and enable significantly prolonged retention time at the target site, thereby reducing the frequency
of drug administration.14
Cyclodextrins are circular sugar compounds that have
the property of forming water-soluble inclusion complexes
to enhance the aqueous solubility of lipophilic compounds.
Oculis is developing a nanoparticle technology that would
use g-cyclodextrin nanoparticle/microparticle eyedrops to
deliver drugs to the anterior and posterior segments. The
technology has been used successfully to deliver dexamethasone and dorzolamide, and is currently being explored to
deliver other drugs to the back of the eye.15,16
Replenish has developed the MicroPump, a refillable
implant that dispenses nanoliter-size doses as required.17
pSivida’s Durasert technology is a miniaturized, injectable
sustained-release drug delivery system in use in the fluocinolone acetonide implant 0.19 mg.18 DSM Biomedical is
developing customized polymeric delivery systems, adding
to this range of products.