Eye drops and ointments are the most widely used ophthalmic drug delivery systems (approximately 90%)18 due to their low production cost and ease of administration (Figure 1). Nevertheless, solutions have very low ocular bioavailability because of significant precorneal drug loss through tearing, blinking, systemic elimination, and tear renewal18. Frequent administrations are needed to maintain effective drug concentrations, leading to low therapeutic adherence and consequent therapeutic failure.

Figura 1.

Ocular routes for drug delivery systems53.

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One of the most frequently used techniques to increase ocular surface contact time is the use of traditional viscous agents such as hydroxymethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, polyethylene glycols, and polyvinylpyrrolidone. Natural polymers are also used such as hyaluronic acid, Veegum®, alginates, xanthan gum, gelatin, acacia, and tragacanth21,45.

Ophthalmic emulsions improve the solubility and bioavailability of insoluble drugs, provide sustained release, improve corneal absorption, and prolong precorneal residence time. In ophthalmology, o/w emulsions are preferred over w/o emulsions because of better tolerability and decreased ocular irritation due to the external aqueous phase46. Suspensions can be used as an alternative vehicle with low-solubility drugs, thus increasing the drug particle retention time in suspension as well as contact time. Table 1 shows some examples of ophthalmic emulsions and suspensions currently available on the market.

After solutions and suspensions, ophthalmic ointments are the most popular dosage forms. The vehicle/base for ophthalmic use must not cause eye discomfort and must be compatible with the rest of the formulation components. There is a wide variety of ophthalmic ointments available on the market, most of which have anti-infective, anti-edemic, or anti-inflammatory properties (Table 1). There has been a recent increase in the use of water-soluble bases known as gels because of their advantages over vaseline bases, such as better spreading capacity and their characteristics of pH, lubricity, stability, and low irritability. Polymers used for the preparation of gels generally include PEG 200, PEG 400, carboxymethyl cellulose, carbopol, methyl polymethacrylate, and Lutrol FC-127. These polymers also have mucoadhesive properties that improve drug contact time21. Recently, hospital pharmacy services have begun to include these kinds of ingredients in compounded preparations, such as the use of hyaluronic acid in artificial tears and carboxymethyl cellulose in the production of vancomycin and cysteamine eye drops47.

Another strategy is the use of prodrugs, such as the prostaglandin F2α analogues Bimatoprost (Lumigan®), Travaprost (Travatan®), and Latanoprost (Xalatan®), which are used to reduce intraocular pressure in glaucoma. Furthermore, the Food and Drug Administration (FDA) of the United States has authorized loteprednol etabonate (Lotemax®), a topical corticosteroid derived from the chemical structure of prednisolone, for the treatment of eye allergies and inflammations, although it is not available in the European market48.

Advances have recently been made in research on nanocarriers. These systems allow the administration of a wide variety of active ingredients (including macromolecules) providing stable conditions for labile compounds and better control of drug delivery, thus improving ocular bioavailability. There is a wide variety of components within this group such as polymeric nanoparticles, lipid nanoparticles, cyclodextrins, liposomes, niosomes, dendrimers, nanosuspensions, and emulsions21,44,49, all of which are currently under investigation. These types of systems could be used in the field of compounding, such as cyclodextrins50,61, which reduce the toxicity of active ingredients52 and enhance the solubility of molecules that are barely soluble in vehicles used for ophthalmic administration.

Contact lenses are medical devices that can be loaded with active ingredients, thereby acting as non-invasive drug-delivery systems and providing sustained release in tear fluid located between the cornea and the lens54. Generally, drugs and polymers used for these lenses have low affinity. Thus, to achieve controlled sustained release, a series of modifications are needed such as the incorporation of polymeric nanoparticles, microemulsions, micelles, liposomes, diffusion barriers (e.g. vitamin E) and so on, or the use of sophisticated loading techniques such as molecular imprinting, drug-loaded films, ion ligand polymeric systems, or supercritical fluid technology55,56. When such modifications are introduced, it is essential that aspects such as water content, mechanical properties, ionic permeability, transparency, and oxygen permeability remain unchanged. Up to the present, hindrances to their commercialization have included issues such as drug stability during processing/ manufacturing, achieving zero-order release kinetics, avoiding drug release during the post-manufacturing monomer extraction step, protein adherence, drug release during storage, and cost-benefits46. However, they have potential applicability in the field of ophthalmic compounding, because drugs and excipients can be easily loaded onto them under sterile conditions as part of a relatively simple low-cost formulation process. Thus, an ophthalmic drug delivery system could be made available that is easy and comfortable to administer to the patient and has a dosing schedule that leads to better adherence than that obtained under frequent instillation of ophthalmic drops. These aspects would be of interest in the setting of severe eye infections or rare diseases such as ocular cystinosis.

The goal of ocular inserts and implants is to improve bioavailability and achieve sustained drug delivery. In order to administer medications to the anterior segment of the eye, these systems can be placed under the eyelid, at the bottom of the conjunctival sac, in the anterior chamber, in the subconjunctival space, or in the episcleral region (Figure 2). However, it is difficult to develop implants for the anterior chamber, because they can be susceptible to movement due to the low viscosity of the aqueous humor, causing irreversible damage to endothelial cells.

Figura 2.

Overview of drug delivery devices. a) Eye drops. b) Drug-loaded contact lenses. c) Conjunctival insert, such as Ocusert®. d) The OphthaCoil® conjunctival insert: a device placed behind the lower eyelid in the fornix conjunctiva. e) Conjunctival tablet, Lacrisert® or Mydriasert®: these tablets are placed in the inferior conjunctival fornix. f) Retrisert intravitreal insert: implanted in the vitreous chamber and sewn to the sclera. g) Punctal plug, such as Dextenza or Evolute. h) Intravitreal insert, such as Illuven or Surodex®: implanted or injected into the vitreous chamber. i) Intravitreal injection.

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These devices can be biodegradable or nonbiodegradable (Table 2). Biodegradable or resorbable devices are noninvasive and do not need to be removed. However, most of these devices have limited action time and therefore may require frequent administration. Furthermore, the complete material and its metabolites must not be toxic. Other challenges include the prevention of accidental device loss and increased tear production after placement, which increases the risk of massive drug release57. The Ocusert® system was the first commercially available ocular insert for the treatment of glaucoma. This ocular therapeutic system delivers a small amount of pilocarpine over one week. It consists of two ethylene-vinyl acetate copolymer membranes that provide zero-order kinetics58. This insert was withdrawn from the market in 1998 as a consequence of the adverse effects of pilocarpine, such as eyebrow pain and miosis18.

The only resorbable conjunctival device on the market is Lacrisert®, which is a small hydroxypropyl cellulose tablet placed in the inferior conjunctival fornix. It slowly dissolves and creates an artificial tear film to treat dry eye59. However, it can cause blurred vision, leading to device removal in 8.7% of patients60. Another cul-de-sac implant is DSP-Visulex, which has currently completed a phase-II clinical trial for the treatment of anterior uveitis with dexamethasone (NCT02309385)61.

Nonresorbable devices form another group. These include rod-shaped devices, which are placed in the superior or inferior conjunctival fornix to administer drugs through the noncorneal absorption route. Since 2004, Mydriasert® has been available on the European market. It is an ethylcellulose tablet loaded with tropicamide hydrochloride and phenylephrine to obtain mydriasis two hours before surgery. However, there are no significant differences in pupil dilation between topical mydriatic eye drops and Mydriasert®, although its dilation speed is slower62. Another type of device is OphthaCoil®, a spiral stainless steel wire, which is placed in the lower conjunctival sac. It can carry medications on its inner lumen (loaded in microspheres or filaments) or outside on the SlipSkin® lining. These devices have been tested with pradofloxacin and mydriatic agents (phenylephrine hydrochloride and tropicamide) in Beagle dogs63 and horses64.

The Helios™ device consists of a polypropylene support ring within a silicone matrix loaded with bimatoprost. The results of clinical trials showed that its placement in the eye reduced intraocular pressure in glaucoma patients over six months. However, no significant differences were found between this device and regular 0.5% preservative-free timolol ophthalmic solution. The dropout rate was higher among patients with the Helios device. The main adverse event was mucus discharge65.

Punctal plugs are another type of ocular device that have shown potential as drug delivery systems. These plugs are small biocompatible implants that were initially used to treat dry eye by inserting them into the tear ducts or to block tear drainage. They have the advantages of being non-invasive and maintaining the sustained release of the drug through diffusion. However, they have an increased risk of associated complications, such as conjunctivitis, corneal abrasion, tear duct obstruction, excessive tearing, and plug extrusion42. The materials used in their preparation include silicone, hydroxyethyl methacrylate, and polycaprolactone, but they require removal after the complete release of the active ingredient. Clinical trials are currently underway on the administration of latanoprost, bimatoprost, olopatadine, moxifloxacin, and cyclosporine A18. In 2018, the FDA authorized the marketing of Dextenza®, which contains dexamethasone 0.4 mg for the treatment of postoperative inflammation and pain. However, this format is not available in the European market.

The transfer of these types of devices and implants to the setting of ophthalmic compounding formulation is unlikely because of the complexity of their preparation and sterilization, which would require equipment not currently available in hospital pharmacy services.

In intravitreal administration, the needle is inserted perpendicular to the sclera, between the horizontal and vertical rectus muscles, in order to release the drug in the vitreous chamber where it is distributed and reaches different targets in the posterior eye segment67 (Figure 1). Depending on the nature of the drug and the formulation used, the vitreous humor can act as an important barrier to the release of the drug or its influence may be insignificant15.

After intravitreal administration, drug concentrations at the blood-ocular barriers are clearly higher than those obtained after topical or systemic administration. At this level, drug clearance can occur through the anterior or posterior pathways. Any drug can pass through the anterior route by diffusion through the vitreous humor to the posterior chamber, where the aqueous humor is located, and then eliminated through the trabecular meshwork. However, the posterior route is only available to those drugs that are capable of crossing the endothelium and epithelium that form the blood-ocular barriers. Although these blood-ocular barriers do not allow the passage of proteins and large molecules, they do allow the passage of small molecules15. As a consequence, the clearance of small molecules from the vitreous is much faster than that of molecules with high molecular weights15,53,68.

A priority in AMD research is to decrease the number of visits to the ophthalmologist and the number of intravitreal injections administered69. In this sense, the need to develop new intravitreal drug delivery systems is based on the fact that reductions in the frequency of administration decreases the risk of associated adverse effects and optimizes healthcare costs5. Thus, the vast majority of intravitreal drug delivery systems have been studied using anti-VEGF drugs.

There are various challenges related to the design of new intravitreal drug delivery systems. On the one hand, the size of these systems must be of the order of micrometers or nanometers to fit inside the vitreous chamber, however, they must be also able to contain the appropriate dose to obtain effective concentrations over long periods of time. On the other hand, sustained-release antibody formulations have to maintain antibody stability and bioactivity during storage and release in vivo, which represents another relevant challenge to their development70. Therefore, although numerous intravitreal delivery systems are under research, most of them are in very early stages and only a few have been tested in clinical trials5. Intravitreal anti-VEGF drug delivery systems in development include hydrogels, liposomes, microparticles, nanoparticles, implants, and composite systems (i.e. combinations of two of the foregoing systems)71.

At the clinical level, implants are the only delivery systems that have been marketed for intravitreal administration. They are small solid devices that are surgically implanted or injected into the vitreous humor46. In Europe, commercial implants are currently available that provide the prolonged release of dexamethasone (Ozurdex®), fluocinolone (Iluvien®), and ganciclovir (Vitrasert® 4.5 mg, not marketed in Spain) (Table 3). However, there are no implants with anti-VEGF antibodies currently on the market71.

Some implants for the treatment of AMD are under research. The NT/503 cell line is loaded into an encapsulated-cell technology delivery system, implanted into the vitreous cavity every 12 weeks, and produces VEGF antagonists that are released into the retina. This device underwent phase I/II clinical trials: however, although the procedure seemed well tolerated, the phase II trial was halted due to lack of reproducible long-term efficacy72. We also draw attention to the Port Delivery System, which is a permanent and reusable drug reservoir that is surgically implanted through an incision in the sclera. It is loaded with ranibizumab solution 20 µL (100 mg/mL) that is released into the vitreous through a semipermeable membrane by passive diffusion. The device carries a customized needle that cleans the device and refills it with ranibizumab. This device is currently being tested in the ARCHWAY phase-III clinical trial (NCT03677934)73.