Eyedrop therapy involves periodic delivery of relatively large quantities of a drug to overcome low ocular bioavailability due to various factors, such as tearing and blinking, nasolacrimal drainage, conjunctival blood and lymph flow, metabolic degradation, and corneal and blood–aqueous barriers. The high peak drug levels attained with bolus dosing can cause local and systemic side effects, such as induced accommodation producing brow ache, which can occur after pilocarpine use. In addition, drug concentration in the eye can vary significantly because of variations in application technique and patient adherence to dosing amounts and schedules. Thus, there is a need for an efficient delivery system that can provide controlled release of a drug with a reduced dosing frequency.
Devices have been developed that deliver an adequate supply of medication at a steady-state level, achieving beneficial effects with fewer adverse effects. In the 1970s, the first steady-state drug delivery system, a nonbiodegradable insert designed to deliver pilocarpine at a steady rate of 40 μg/hr, became available. This device was discontinued as the use of pilocarpine decreased. Ocular inserts currently in development or under investigation are cylindrical in shape and are placed in the fornix for prolonged drug release. They can be categorized as soluble or insoluble:
Soluble inserts release the drug via interaction between the polymeric matrix of the device and the tear film. Removal of these inserts is unnecessary.
Insoluble inserts may achieve a more constant rate of drug release than soluble inserts, but removal of the device is required.
Ocular inserts have the advantages of prolonged and steady delivery of drugs, which can improve patient compliance. However, they have the potential for patient discomfort such as foreign-body sensation.
To circumvent the repeated injections that are required with intraocular injection of a drug, various implantable devices were developed for sustained drug delivery. The first-available sustained-release implant was the ganciclovir intravitreal implant for treatment of cytomegalovirus (CMV) retinitis. An ethylene vinyl acetate disc with a PVA coating served as the drug reservoir. The thickness of the PVA lid regulated the delivery of ganciclovir to the target tissue. After surgical implantation, the device delivered a steady source of ganciclovir for 5–8 months. The ganciclovir intravitreal implant was discontinued after the patent expired in 2015. Current intraocular sustained-release products approved by the FDA include 2 fluocinolone acetonide intravitreal implants (0.59 mg and 0.19 mg) and a dexamethasone intravitreal implant.
The 0.59-mg fluocinolone acetonide implant, a nonbiodegradable intraocular polymer implant requiring surgical placement in the pars plana region, is approved by the FDA for the treatment of chronic noninfectious posterior uveitis. It was designed to release fluocinolone acetonide at a nominal initial rate of 0.6 μg/d, decreasing over the first month to a steady state between 0.3 and 0.4 μg/d over approximately 30 months.
The 0.19-mg fluocinolone implant, delivered by intravitreal injection, has a nonbioerodable tube of polyimide and a permeable membrane of PVA at one end that releases the medication. It was approved by the FDA for the treatment of diabetic macular edema in patients who are not steroid responders. The implant releases fluocinolone acetonide at an average rate of 0.2 μg/d for 36 months.
The 0.7-mg dexamethasone implant is a biodegradable poly(lactic-co-glycolic acid) (PLGA) matrix loaded with dexamethasone for injection into the vitreous cavity. The polymer degrades to lactic acid and glycolic acid, and dexamethasone is slowly released within the vitreous cavity. The implant is indicated for the treatment of macular edema secondary to retinal vein occlusion, noninfectious posterior uveitis, and diabetic macular edema. Various biodegradable and nonbiodegradable implants designed for sustained release of single or multiple medications are under development.
Intraocular lenses and other sustained-release systems
Sustained-release systems that use biodegradable polymers entrapped with triamcinolone acetonide or antibiotics and are attached to the periphery or haptics of an artificial intraocular lens are under investigation to prevent intraocular infection and control postoperative intraocular inflammation. Other research efforts include development of an intraocular lens prepared with biomaterials that not only allow high transmittance at visible wavelengths but also can be loaded with dexamethasone to achieve sustained release of this drug after cataract surgery.
Intraocular sustained-release devices are being studied as alternatives to glaucoma medical therapy that has been shown to have poor patient compliance. Products under investigation include injectable sustained-release biodegradable implants through which various hypotensive medications can be delivered into the anterior chamber or supraciliary space or beneath the conjunctiva to achieve a sustained reduction of intraocular pressure for months.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.