Advances in the use of prodrugs for drug delivery to the eye

Abstract

Ocular drug delivery is presented with many challenges, taking into account the distinctive structure of the eye. The prodrug approach has been, and is being, employed to overcome such barriers for some drug molecules, utilizing a chemical modification approach rather than a formulation-based approach. A prodrug strategy involves modification of the active moiety into various derivatives in a fashion that imparts some advantage, such as membrane permeability, site specificity, transporter targeting and improved aqueous solubility, over the parent compound. Areas covered: The following review is a comprehensive summary of various novel methodologies and strategies reported over the past few years in the area of ocular drug delivery. Some of the strategies discussed involve polymer and lipid conjugation with the drug moiety to impart hydrophilicity or lipophilicity, or to target nutrient transporters by conjugation with transporter-specific moieties and retrometabolic drug design. Expert opinion: The application of prodrug strategies provides an option for enhancing drug penetration into the ocular tissues, and overall ocular bioavailability, with minimum disruption of the ocular diffusion barriers. Although success of the prodrug strategy is contingent on various factors, such as the chemical structure of the parent molecule, aqueous solubility and solution stability, capacity of targeted transporters and bioreversion characteristics, this approach has been successfully utilized, commercially and therapeutically, in several cases.

Keywords: Lipid prodrug; polymer-conjugated prodrug; retrometabolic drug design; transporter targeted drug delivery.

Fig. 1.

Biological barriers of the eye (tight barriers are indicated in red, others in green; route of elimination). The main pathway for drugs to enter the anterior chamber is via the cornea (1). Some large and hydrophilic drugs prefer the conjunctival and scleral route, and then diffuse into the ciliary body (2). After systemic administration small compounds can diffuse from the iris blood vessels into the anterior chamber (3). From the anterior chamber the drugs are removed either by aqueous humor outflow (4) or by venous blood flow after diffusing across the iris surface (5). After systemic administration drugs must pass across the retinal pigment epithelium or the retinal capillary endothelium to reach the retina and vitreous humor (6). Alternatively, drugs can be administered by intravitreal injection (7). Drugs are eliminated from the vitreous via the blood–retinal barrier (8) or via diffusion into the anterior chamber (9).

Figure 2.

Supramolecular nanofibers of Triamcinolone Acetonide 1. The first step involves a one-step synthesis of Succinated Triamcinolone Acetonide from parent drug Triamcinolone Acetonide, in the presence of pyridine at room temperature for 3 h. 2. The second step involves formation of TA hydrogel from Succinated TA in PBS buffer solution (pH = 7.4) for about 35h at 37°C.

Figure 3.

Conversion of Pro-prodrug/ double prodrug UNIL088 to Cyclosporine A by formation of pSer-Sar-CsA as intermediate by enzymatic and chemical reactions.

Figure 4.

The retrometabolic design loop 1. Chemical delivery systems (CDS) structurally modify the active drug moiety by attaching covalently to a target function (T) responsible for site specificity and a modifier function (F), to prevent premature metabolic conversions. On approaching the site of action, CDS undergo metabolic conversions releasing F, and T. 2. Soft Drug strategy involves selection of one of the inactive natural metabolites of the drug for retrometabolic design resulting in formation of the soft drug, which after metabolism gives the same inactive metabolite.

Figure 5.

Biotinylated Lipid prodrugs: Biotin-12-Hydroxystearic acid-ACV. The drug moiety, Acyclovir, is conjugated to the biotinylated lipid raft, 12- Hydroxystearic acid. The lipid raft enhanced prodrug-membrane protein interaction and the biotin conjugation improved the SMVT transporter targeting.