Ocular Medication Routes of Administration: Comparison
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Ocular drug administration encompasses a range of routes, each with its own advantages and limitations. The available methods include systemic delivery (such as oral, intravenous, and subcutaneous routes) as well as local delivery options (including topical eye drops, periocular or intravitreal injections, and intravitreal implants). While these approaches can be effective in delivering medications to the eye, they also have inherent drawbacks, which will be explored in greater detail in this entry. Notably, understanding the strengths and limitations of these ocular drug administration routes is crucial for optimizing therapy and achieving the desired therapeutic outcomes while minimizing potential adverse effects.   

  • Ocular drug administration
  • Systemic delivery
  • Topical eye drops
  • Periocular injections
  • Intravitreal injections
  • Therapeutic goals
  • Ophthalmology

1. Route of Administration

Various routes exist for ocular medication administration, each with distinct pros and cons. Systemic delivery (oral, intravenous, subcutaneous) and local methods (topical drops, periocular/IV injections, IV implants) are commonly used [20][1]. However, these methods have limitations. Table 1 and Figure 1 provide an overview of the advantages and disadvantages of different ocular drug administration approaches [2,21][2][3].

 

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Figure 1. An Overview of Various Ophthalmic Medication Delivery Routes. This figure illustrates the range of administration methods used in ophthalmic medicine, including topical, subconjunctival, intravitreal, suprachoroidal, and subretinal techniques.

Table 1. Comparison of Different Ocular Drug Administration Methods [2,20,21][1][2][3].
Injection Method Advantages Disadvantages
Topical Eye Drops [22][4] Prevalent, well-known method Low bioavailability to posterior segment tissues
Non-invasive method for ocular drug delivery Short duration of action, requiring frequent administration
  Relies on patient’s compliance
  Local complications (ocular surface irritation, cataracts, ocular hypertension, periocular aesthetic issues)
Systemic Drug Administration Noninvasive and potentially patient-preferred High doses often required due to reduced accessibility to targeted ocular tissues
Usable as standalone or in combination with topical delivery Potential systemic side effects due to high dosage, necessitating safety and toxicity considerations
  Effective bioavailability is challenging due to blood–ocular barriers
Intravitreal Injection [23][5] Office-based, outpatient procedure Requires frequent in-office visits
High bioavailability (bypass corneal and blood–retinal barriers) Potential for severe complications (Endophthalmitis, retinal detachment, vitreous hemorrhage)
Fewer systemic side effects compared to oral or IV administration Local complications (increased IOP, cataract formation)
Rapid therapeutic onset Possible post-injection floaters
  Systemic absorption and side effects can still occur
Subretinal Injection [24][6] Targeted treatment for the RPE and outer retina Invasive procedure, requires vitrectomy
Reduced immune reactions for gene therapy using viral vectors (due to injection in an immune-privileged site)

Limited distribution of injectate within subretinal space; effects confined to injection site

 

1.1. Topical Administration

Topical administration, primarily through eye drops, is a commonly used non-invasive approach for ocular drug delivery. However, it presents challenges due to the eye's anatomy and physiology.

The concentration gradient from the tear reservoir to the cornea or conjunctiva drives passive absorption, but only a small fraction of the administered drop (approximately 20%) is retained in the eye [25][7]. Within a few minutes, about half of the medication leaves the eye, with a rapid turnover rate of around 15% per minute. Factors like reflex tearing, consecutive dosing, and the small cul-de-sac of the eye contribute to fast tear turnover, accelerating drug clearance and hindering effective absorption [2,21][2][3].

Furthermore, drugs must traverse the hydrophobic tight junctions formed by the epithelium and endothelium, as well as the hydrophilic stroma layer of the cornea (Figure 3) [26][8]. The low permeability of the cornea and sclera limits drug penetration, reducing the bioavailability of topically administered drugs.

Due to the barriers posed by the cornea and high tear turnover rates, frequent and high-dose applications are often required for topical administration. This can lead to local and systemic side effects, potentially compromising patient compliance [27][9]. Studies have shown that medication non-compliance rates in the general population are approximately 80% [28][10], and these challenges are even more pronounced in certain populations, such as the elderly and individuals with physical disabilities.

Additionally, topical drugs may affect unaffected tissue, resulting in side effects. For example, chronic use of topical steroids can lead to complications like cataracts and ocular hypertension [22][4]. Similarly, topical prostaglandins can cause undesirable periocular aesthetic concerns [29][11].

Although topical application is a primary method of ocular drug delivery, these complexities underscore the need for advancements in drug delivery methods to overcome the limitations associated with topical administration.

1.2. Systemic Administration

Oral delivery has been investigated as a potential route for ocular drug administration, either alone or in combination with topical delivery [30,31,32,33][12][13][14][15]. While it offers a non-invasive option for managing chronic retinal diseases, oral administration has limitations. It has reduced accessibility to targeted ocular tissues, requiring high doses for therapeutic effectiveness. However, high dosages can lead to systemic side effects, necessitating careful consideration of safety and toxicity [34,35][16][17].

For oral delivery to be effective in ocular applications, achieving high oral bioavailability is crucial. Additionally, after oral absorption, molecules must traverse systemic circulation and overcome the blood-ocular barriers, including the blood-aqueous and blood-retinal barriers (Figure 2). The blood-retinal barrier consists of an inner barrier, protected by the fenestrated endothelium of retinal vasculature, and an outer barrier, maintained by tight junctions within the retinal pigment epithelium (RPE). These protective ocular structures present significant challenges for systemic drug administration [34,35][16][17].

 

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Figure 42. Anatomical and Physiological Barriers in the Eye Impacting Drug Delivery.

Systemic medications, including steroidal and nonsteroidal anti-inflammatory drugs, as well as immunomodulatory agents (both biologic and nonbiologic), are effective for treating uveitic macular edema (UME). However, they are typically reserved for bilateral disease or cases unresponsive to local therapy due to potential adverse effects (AEs) such as infections and gastrointestinal (GI) disturbances [20,36,37][1][18][19]. Additionally, the use of nonsteroidal anti-inflammatory drugs and systemic immunomodulatory agents, either alone or in combination with steroids, may further increase the risk of GI disturbances [20,36,37][1][18][19].

1.3. Periocular Injection

Periocular drug administration offers an alternative to topical and systemic dosing, which struggle to achieve therapeutic drug concentrations in the posterior segment [2]. Compared to intravenous administration, periocular routes (subconjunctival, subtenon, retrobulbar, and peribulbar) are less invasive [2].

Subconjunctival injections can enhance absorption of water-soluble drugs by bypassing the conjunctival epithelial barrier. However, access to the posterior eye segment remains limited due to various barriers, including dynamic factors such as conjunctival blood and lymphatic circulation [38,39,40][20][21][22]. These dynamic barriers contribute to rapid drug elimination, reducing ocular bioavailability and vitreous drug levels after administration [38,39,40][20][21][22]. Although some molecules can reach the neural retina and photoreceptor cells through the permeable sclera [20[1][23],41], the high blood flow in the choroid can remove a significant portion of the drug before it reaches its target. Moreover, the presence of tight junctions within the retinal pigment epithelium forms blood-retinal barriers that restrict drug availability to the photoreceptor cells.

1.4. Intravitreal Injection

IV administration is widely used as a first-line therapy for various ocular conditions, including neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and macular edema secondary to retinal vein occlusion (RVO) [42][43][44][24][25][26]. It offers advantages such as direct drug delivery to the retina and vitreous, bypassing corneal and scleral barriers, and circumventing the blood-retinal barrier. These benefits ensure high bioavailability, rapid therapeutic effects, and improved patient compliance compared to topical eyedrops [45][27].

However, IV injections have drawbacks and potential complications. Severe complications include the risk of endophthalmitis, retinal detachment, and vitreous hemorrhage. IV steroids specifically can cause increased intraocular pressure and cataract development [43][25]. Minor side effects, such as floaters, and the potential for systemic absorption and associated side effects can also impact patient satisfaction and treatment adherence [43][25].

Another challenge with IV administration is the need for frequent injections due to the short half-life of drugs [46][47][48][28][29][30]. After injection, drugs are eliminated either anteriorly or posteriorly. Anterior elimination involves diffusion through the vitreous, aqueous turnover, and uveal blood flow. Posterior elimination requires permeation through the blood-retinal barrier, which can be passive or actively mediated. Hydrophilic drugs with larger molecular weights have longer half-lives, while hydrophobic drugs with smaller molecular weights have shorter half-lives, necessitating more frequent injections. The burden of regular in-office visits and patient-specific factors like age and prior vitrectomy can further complicate the treatment regimen and decrease compliance [48][49][30][31].

To overcome the limitations of short treatment duration and frequent in-office visits, intraocular implants have been developed. The Multicenter Uveitis Steroid Treatment (MUST) trial assessed a fluocinolone acetonide (FA) intraocular implant that releases the drug over approximately 30 months [50][32]. In the short term, the FA implant demonstrated superior efficacy in controlling uveitic inflammation and reducing macular edema compared to systemic corticosteroids, but the differences diminished after 24 months. However, the FA implant was associated with a fourfold increase in the risk of elevated intraocular pressure (IOP) requiring intervention. Extended follow-up after seven years revealed that patients receiving systemic therapy had better visual acuity than those with IV FA implants [51][33].

In the realm of gene therapy, intravitreal injection of an anti-VEGF transgene product (Adverum Biotechnologies) has shown promise but raises concerns about significant inflammatory responses [52][53][54][55][34][35][36][37]. The vitreous presents challenges for retinal gene delivery due to components like hyaluronan, which can lead to aggregation and immobilization of DNA/liposome complexes [56][57][38][39]. The inner limiting membrane (ILM) and the retinal pigment epithelium (RPE) also act as barriers to retinal gene delivery and drug transport to the choroid, respectively [58][9][40][41].

Emerging alternatives like subretinal and subconjunctival (SC) drug delivery hold potential for longer-lasting effects, reducing injection frequency, and minimizing gene therapy-induced inflammation [59][42].

1.5. Subretinal Injection

Subretinal delivery is a promising approach for retinal gene therapy, particularly for retinal degeneration and vascular diseases. This method involves directly introducing viral vectors into the immune-privileged subretinal space, allowing targeted treatment for the retinal pigment epithelium (RPE) and outer retina while minimizing immune reactions [24][6].

The FDA-approved gene therapy Voretigene neparvovec-rzyl (Luxturna) for RPE65-associated inherited retinal dystrophy has shown promising outcomes [60][61][43][44]. Gene therapy also holds potential for conditions like diabetic retinopathy (DR) and age-related macular degeneration (AMD), suggesting the possibility of a single-dose treatment for these chronic diseases. Early studies using subretinal adenoviral vector anti-VEGF gene therapy have demonstrated a significant reduction in treatment burden and a favorable safety profile for neovascular AMD [62][45].

However, it's important to acknowledge that subretinal delivery presents its own challenges. It requires an invasive vitrectomy procedure for administration, and the localized distribution of the injected material may limit therapeutic effects to the vicinity of the injection site [59].[142].

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