Posterior drug delivery via periocular route: challenges and
opportunities
Waite, D., Wang, Y., Jones, D., Stitt, A., & Thakur, R. (2017). Posterior drug delivery via periocular route:
challenges and opportunities.
Therapeutic Delivery
,
8
(8), 685-699. https://doi.org/10.4155/tde-2017-0097
Published in:
Therapeutic Delivery
Document Version:
Peer reviewed version
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Download date:10. Aug. 2022
1
Posterior Drug Delivery via Periocular Route: Challenges and
Opportunities
Abstract
Drug delivery to the posterior segment via periocular route is a promising route for delivery of
a range of formulations. In this review, we have highlighted the challenges and the
opportunities of the posterior segment drug delivery via the periocular route. Consequently,
we have discussed different types of periocular routes, physiological barriers that limit effective
drug delivery, practical challenges regarding patient compliance and acceptability and recent
advances in developing innovative strategies to enhance periocular drug delivery. We
conclude with a perspective of how we envisage the importance of understanding complex
barrier functions so as to continue to develop innovative drug delivery systems.
Keywords: periocular, posterior segment, drug delivery.
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Introduction
Drug delivery to the eye, even to the present day, is a difficult task and even more so when it
comes to treating diseases and disorders that require drug delivery to the posterior segment
[1]. The anatomical and physiological barriers that the ocular environment presents are unique
and have led to various routes of administration, each with its own advantages and
disadvantages [2]. Despite the issues in getting therapeutic drug levels in this part of the eye,
the importance of successful delivery to the posterior segment cannot be underestimated, with
the treatment of many proliferative, vascular and degenerative ocular diseases requiring it as
a matter of course [3]. This review paper will highlight some of the major posterior segment
diseases, routes of administration used to treat them – with a particular focus on the periocular
route and the challenges it presents. Current research into this area is also discussed, to
establish whether these challenges are being overcome, to and the future direction in
periocular drug delivery.
Diseases of the Posterior Segment
Most prevalent eye diseases that cause visual impairment typically originates in the posterior
segment of the eye (or back of the eye) and include age-related macular degeneration (AMD),
diabetic retinopathy (DR), diabetic macular edema (DME), uveitis and retinitis. AMD is the
leading cause of blindness among the aging population. A chronic disease of the central retina,
specifically the macula, this disease is one of the leading causes of blindness and manifests
itself in two broad types: neovascular (“wet”) AMD or geographic atrophy (“late dry”) AMD. In
the “wet” form, choroidal neovascularization breaks through the retina leading to leaking fluids,
lipids and blood resulting in fibrous scarring. The “late dry” form manifests as progressive
atrophy of the RPE, choriocapillaris, and photoreceptors. Treatment methods for neovascular
AMD consist of laser photocoagulation, photodynamic therapy and more recently the use of
anti-VEGF (vascular endothelial growth factor) therapies [4]. The latter of these treatments is
particularly significant here, as ranibizumab and bevacizumab, two of the drugs of this type,
are currently delivered via intravitreal injection, showing the importance of delivery of the
therapeutic agent into the ‘local’ area of the posterior segment for a therapeutic effect [5].
Uveitis is simply inflammation of the uvea, a structure not just confined to the posterior
segment of the eye, resulting in many sub-types of this [6], with posterior uveitis being the
focus here. Posterior uveitis involves inflammation of the choroid, retina or both or the retinal
vessels, with infection being the cause in over 40% of cases and includes toxoplasmosis,
tuberculosis, candida, herpes simplex, zoster or cytomegalovirus [7]. Typically, this disease is
treated with corticosteroids and immunosuppressant agents. While periocular delivery of
steroids is an option; the oral route is preferred due to issues surrounding administration and
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potential for ocular hypertension [8]. Some studies have also highlighted the use of intravitreal
steroid injections as a treatment option, albeit with the recommendation being as a short-term
treatment [9].
DR is commonly linked to patients that have diabetes mellitus [10], and it is the leading cause
of blindness in adults of working age [11]. The loss of vision associated with this can be due
to the non-clearance of vitreous humor or fibrosis, which then leads to retinal detachment
through traction. Blood vessels can then leak causing permanent central vision loss-diabetic
macular edema [12]. DME is the leading cause of visual impairment that occurs with DR. Lots
of factors play a role in the development of the disease including; the degree of retinopathy,
hypertension, glycemic control or lack thereof blood lipid and albumin levels and fluid retention
[11,13]. Treatment options consist of focal or grid laser photocoagulation depending upon the
nature of the DME, with the diffuse form being treated with the grid laser to cover the whole
area [14]. Pars-plana vitrectomy has to be used in some cases to prevent visual loss, and
intravitreal and sub-tenon delivery of corticosteroids have also been used [14,15]. Anti-VEGF
treatments, again delivered by intravitreal injection, are also being investigated as treatment
options [16]. Once again, while the treatments show promise, delivery of the drugs to the
posterior segment in a safe and repeatable fashion is the issue.
The diseases alluded to above and many others that affect the posterior segment of the eye
have an influence on the patients’ vision and so have a significant impact on quality of life. As
a result, treatment of these is of the utmost importance, requiring successful delivery of
appropriate drugs, within the therapeutic window in a safe and repeatable fashion. While many
drugs have shown promise in treating some of these, effective and safe delivery to the
posterior segment is proving difficult.
Drug Delivery to the Posterior Segment of the Eye
Drug delivery to the eye can be achieved through different routes (Fig. 1), as discussed below.
Topical Route
Topical delivery is the most commonly used method of ocular drug delivery, more often for
delivery to the anterior segment, to treat diseases such as glaucoma and conjunctivitis. Certain
drugs are delivered via this route for the treatment of issues in the posterior segment.
However, it is highly inefficient as less than 5% of the drug reaches the aqueous humor, with
an even smaller proportion reaching the posterior segment due to a variety of barriers [17].
These include the dilution and flushing out of the drug by the tears, nasolacrimal drainage and
tear turnover [18].
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Moreover, the cornea is a very effective barrier, possessing both lipophilic epithelial and
endothelial layers and a hydrophilic stromal layer in between them, giving extremes of polarity
as drugs would move through it, restricting their movement. There are also tight junctions
present between the epithelial cells, making drug diffusion via the paracellular route difficult.
A particular difficulty is seen with macromolecules, with only those of less than 50,000 Da
being able to move through the stroma [19]. The endothelial layer within the cornea is also
lipophilic, meaning that any drug would need an amphiphilic carrier and to possess both
hydrophilic and lipophilic groups to move through the cornea effectively. Drugs are often
rapidly cleared from the aqueous humor upon penetrating the cornea [20], but diffusion
through the highly dense matrix of the vitreous humor is difficult [21]. Therefore, achieving
therapeutic drug levels in the posterior segment through topical route such as eye drops,
ointments, gels and drug-containing contact lenses is highly problematic.
Systemic Route
Systemic delivery, in the form of a patient taking an oral formulation, would be highly
convenient and acceptable to patients it is not an automatic choice. Only a small proportion of
systemically delivered drug gets to the posterior segment of the eye, largely due to the barrier
properties of the blood-retinal barrier (BRB) [18] and low cardiac output to the retina [22], and
thus large systemic doses are often required to achieve a therapeutically-effective drug
concentration, which in turn can lead to significant side-effects [18]. Indeed, one study showed
the intravitreal drug levels of poorly lipid soluble antibiotics, such as penicillins and
cephalosporins are at maximum 10% of serum levels, resulting in frequent administration
being necessary and systemic side-effects as a result [23]. Furthermore, with many drugs now
being proteinaceous in nature, utilisation of the systemic route would lead to issues such as
denaturation and low therapeutic effect as a result.
Intravitreal Injections
A drug delivery method that involves direct injection of a formulation into the vitreous humor
via the pars-plana (Fig. 1) [24]. It achieves high concentrations of drug in the vitreous and at
the neural retina with less systemic side effects than systemic delivery [25]. Solutions,
suspensions, depots, liposomes and implants have all been delivered by this route, and many
drugs used for the treatment of posterior segment diseases are delivered via this pathway
[26]. However, the drugs of lower molecular weight are rapidly eliminated, thereby frequent
administration becomes necessary, which in turn leads to an increased chance of problems
associated with frequent injections, such as retinal detachment, retinal hemorrhage, and
endophthalmitis [25,27]. There are also barriers to the retinal area, despite the proximity of the
injection site to it. The inner limiting membrane (ILM) is immediately adjacent to both the retina
![Table 1. Benefits and challenges of different routes of drug delivery to the posterior segment of the eye. Adapted with permission [39], 1998, Wiley.](/figures/table-1-benefits-and-challenges-of-different-routes-of-drug-1zda2zsu.webp)