There is no doubt that corneal disease requires treatment, as it can lead to clouding, scarring, distortion, and vision loss. We are aware that there may be obstacles that interfere with patient compliance to prescribed treatments. These include mobility issues that preclude the correct amount of drug from entering the eye, and patient forgetfulness that affects their careful adherence to a drug-dose schedule, among other problems. The good news: Drug-delivery options are available for these conditions for the patients described.

In addition to solving patient adherence issues, drug-delivery options can control the drug-release rate, improve drug penetration, target and enhance drug bioavailability, and reduce adverse effects.

Here, we discuss the individual drug-delivery options in alphabetical order:

Contact Lenses

• Mechanism of action. Contact lenses can be loaded with anti-inflammatory, antibacterial, an immunosuppressant, corticosteroids, and ocular-reducing drugs,¹ eliminating dosage frequency.

Drug absorption and transport to the target ocular tissues take place, increasing ocular bioavailability in the process of wearing contact lenses. Additionally, a drug’s systemic absorption is prevented, and the associated adverse effects are diminished.² Further, drug-eluting contact lenses are envisioned to increase drug retention time and prolong contact lens wear time.^3,4 Incidentally, we are part of a team that has developed dexamethasone-eluting therapeutic contact lenses (D-TCLs).^5-7

• Applicable conditions. Contact lenses have the potential to be exploited as innovative treatment tools for disorders and diseases affecting the anterior chamber and ocular surface. The use of contact lenses as a drug reservoir is a potential therapy option for glaucoma patients. Furthermore, contact lenses can operate as a physical barrier against airborne antigens and as a permanent depot of antihistamines, allowing them to increase the therapeutic efficiency for specific ocular allergic disorders. Incidentally, in March 2022, the FDA approved Acuvue Theravision with ketotifen (Johnson & Johnson Vision Care), a daily disposable contact lens for the treatment of allergic eye itch.

For additional drug-eluting contact lenses to come to the U.S. market, issues of antimicrobial activity and microbial contamination, oxygen permeability, and prolonged and efficient drug release profiles must be evaluated.

Gel

• Mechanism of action. Ocular gel can deliver diverse drugs to distinct corneal regions, making it possible for the ideal medication concentration to reach the site of interest. By combining several ophthalmic medicines, sustained amounts of the bioactive agents might be delivered to the site of interest using ocular gels.⁸

To enhance ocular drug administration, numerous polymeric gels with in situ gelling characteristics have been designed as liquid prescription systems. When these systems are exposed to surrounding stimuli, they undergo a phase change on the ocular surface or conjunctival cul-de-sac to produce a semisolid/viscoelastic material. Thus, ocular gel can solve the issue of patient non-compliance to treatment, as it can decrease dosing, simplifying the treatment regimen. In situ gels don’t require toxic organic solvents or copolymerization catalysts to be formed.

• Applicable conditions. Ocular gel formulations are currently commercially accessible for glaucoma, ocular infections induced by herpes simplex virus infections, as an ocular surface anesthetic during ophthalmologic operations, and for treating the symptoms of bacterial conjunctivitis.

To bring new ocular gels to the U.S. market, toxicity issues caused by repeated and long-term usage must be addressed. Furthermore, due to reflex tears and blinks, the increased viscosity of the gel may create various limits, such as impaired vision and pain to the patient. As a result, a significant viscosity control should be considered throughout the design and optimization of gel formulation to decrease the restrictions to a bearable level.

Injections

• Mechanism of action. Intraocular injections deliver high-drug concentrations to the targeted tissue.⁹ Subconjunctival, intracorneal, intracameral, and intrastromal injections all transport the therapeutic molecule to the desired region. Intrastromal injections, for example, are particularly beneficial for the treatment of fungal keratitis.

Subconjunctival injections have side effects, including bleeding.¹⁰

Intracorneal injections have been linked to corneal edema, fast lytic activity of the corneal stroma, sloughing, and corneal haze.¹¹

Additionally, intrastromal injection using a hypodermic needle has been reported by patients as uncomfortable and intrusive.^12,13

Further, such injections may result in tissue injury, inflammation, and bacterial infections. Generally speaking, intraocular injections can create patient non-compliance with appointments for additional injections, and lower ocular bioavailability.¹⁴

Microneedles can be used for minimally invasive drug administration to the eye.

Composed of metal or polymer and ranging in size from a few micrometers to about 200 µm, microneddles can deliver medication to the site of interest, while bypassing the ocular barriers. Thus, they minimize patient discomfort.

Different forms of drug formulations, including sustained-release depot-forming gels and nanoparticles, have been delivered into the eye through hollow or single solid microneedles.^15,16 One team reported a disposable microneedle as a minimally invasive approach for long-lasting corneal drug delivery.¹⁷

• Applicable conditions. Intrastromal injection of antifungal agents is effective in the resolution of fungal keratitis.

Following cataract surgery, an intracameral injection of cefuroxime is a routine procedure to preclude infection.

An engineered form of fibroblast growth factor 1 that is injected intracamerally is under investigation for regenerating corneal endothelial cells lost due to corneal endothelial dystrophies, such as Fuchs’ endothelial dystrophy.¹⁸

Inserts

• Mechanism of action. Ocular inserts are solid objects implanted into the conjunctival cul-de-sac to discharge bioactive agents continuously for a prolonged period.

Additionally, they reduce the systemic uptake of the drug through the nasal mucosa to the absolute minimum.¹⁹

The Ocusert pilocarpine system (Alza Corp.) was launched as a drug-loaded ocular insert. The medicine was carried in this device by a reservoir encircled by a pair of discharge membranes. It was demonstrated that the procedure required fewer bioactive molecules to have a therapeutic impact, resulting in fewer adverse effects.¹⁹

The insert can move within the eye, which can interfere with vision and cause transient blurring and ocular discomfort. Other problems include irritation, matting, or stickiness of eyelashes; photophobia; hypersensitivity; and eyelid edema and hyperemia. Ocular inserts can also be challenging to fit.^19,20 Further, transient blurring of vision; ocular discomfort or irritation can occur.

• Applicable conditions. Ocular inflammation and pain after ophthalmic surgery, allergic conjunctivitis-caused ocular itching, and moderate-to-severe dry eye disease (DED) patients can benefit from inserts.

Lacrisert (Bausch + Lomb) is a hydroxypropyl cellulose insert approved by the FDA for the treatment of moderate-to-severe DED, including keratoconjunctivitis sicca.

Punctal Plugs

• Mechanism of action. Punctal plugs, available as both dissolvable and semi-permanent, are implanted in the tear ducts to obstruct tear outflow. They range in size from 2 mm to 5 mm.

After the punctum is blocked, more tear fluid is accumulated, keeping the eye moist. Tears are prevented from flowing through the canaliculi via punctal plugs.¹⁹ Pharmaceuticals can be released into the anterior part of the eye.

Dextenza (Ocular Therapeutix) delivers a tapered 0.5 mg dose of the corticosteroid dexamethasone to the ocular surface for up to 30 days. It is FDA approved for the treatment of ocular inflammation and pain post ophthalmic surgery and in October 2021 for the treatment of allergic conjunctivitis-caused ocular itching.

Punctal plugs in general can create dacryocystitis (rare), irritation of the tear duct, watery eyes, and can be challenging to fit.

• Applicable conditions. DED, epiphora linked with stenosis, ocular allergy, and glaucoma patients can achieve relief with punctal plugs.

An Ever-Growing Toolbox

Because patients can have mobility issues that preclude the correct amount of drug from entering the eye, and forgetfulness that affects their careful adherence to a drug-dose schedule, among other hurdles to adhering to their prescribed medication, drug-delivery options are a welcomed addition to our treatment armamentarium.

Add the fact that these drug-delivery systems can control the drug-release rate, improve drug penetration to the desired area of the anterior segment, target and enhance drug bioavailability, and reduce adverse effects, and there’s no doubt ophthalmologists should consider employing them in the aforementioned applicable conditions, while staying abreast of use in additional condtions. CP

References:

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2. Siafaka PI, Yağcılar AP, Üstündağ Okur N. New era of ocular drug delivery systems based on contact lenses. FABAD J Pharm Sci. 2020;45(2): 161-174.
3. Sartini F, Menchini M, Posarelli C, Casini G, Figus M. In vivo efficacy of contact lens drug-delivery systems in glaucoma management. a systematic review. Appl Sci. 2021;11(2): 724.
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5. Ross AE, Bengani LC, Tulsan R, et al. Topical sustained drug delivery to the retina with a drug-eluting contact lens. Biomaterials. 2019;217: 119285.
6. Bengani LC, Kobashi H, Ross AE, et al. Steroid-eluting contact lenses for corneal and intraocular inflammation. Acta Biomater. 2020; 116:149-161.
7. Soeken TA, Ross AE, Kohane DS, et al. Dexamethasone-eluting contact lens for the prevention of postphotorefractive keratectomy scar in a New Zealand white rabbit model. Cornea. 2021;40(9): 1175-1180.
8. Pandey M, Choudhury H, Binti Abd Aziz A, et al. Potential of stimuli-responsive in situ gel system for sustained ocular drug delivery: recent progress and contemporary research. Polymers (Basel). 2021;13(8): 1340.
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16. Guillot AJ, Cordeiro AS, Donnelly RF, Montesinos MC, Garrigues TM, Melero A. Microneedle-based delivery: an overview of current applications and trends. Pharmaceutics. 2020;12(6): 569.
17. Lee KJ, Song HB, Cho W, Kim JH, Kim JH, Ryu WH. Intracorneal injection of a detachable hybrid microneedle for sustained drug delivery. Acta Biomater. 2018;80: 48-57.
18. U.S. Library of Medicine. Clinicaltrials.gov . A Safety and Efficacy Trial of TTHX1114 in People With CED (OPTIC). Accessed Sept. 26, 2022.
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20. Macoul KL, Pavan-Langston D. Pilocarpine ocusert system for sustained control of ocular hypertension. Arch Ophthalmol. 1975;93(8): 587-590.

 

DR. FARHAT is a researcher at Harvard Medical School, where he is developing therapeutic contact lenses. He received the Ph.D. degree in the area of polymer and material science - biomaterials, from a joint supervision between North Carolina State University, USA, and UJM, IMP, Lyon University, France in 2018. His research interests include 3D bioprinting, targeted drug delivery, and tissue engineering.

DR. CIOLINO is a cornea fellowship-trained ophthalmologist and clinician-scientist who is on full-time staff at Massachusetts Eye and Ear/Harvard Medical School. His clinical focus is on corneal transplants, keratoprosthesis, corneal cross-linking, and anterior segment disease. He has a multidisciplinary laboratory at Schepens Eye Research Institute that is focused on translational research. His research interests include keratoprosthesis and ocular drug delivery.