The general goal of ophthalmic drug delivery is to maximize drug levels in the target eye tissues while minimizing the levels in the remainder of the body. Ocular delivery can be achieved by topical administration, systemic administration, periocular injections, and intraocular injections. Topical administration of drugs results in higher drug concentrations in the extrao-cular barriers (conjunctiva, cornea), followed by the anterior chamber and its structures (aqueous humor, lens), with minimal drug entering the poster-
ior ocular structures including vitreous, retina, and choroid. Following systemic administration, the concentration of drug obtained within the eye depends on the blood concentration-time profile of the free drug and the rate of drug clearance from the eye compartments. The blood-ocular barriers, which include the iris blood vessel endothelium, ciliary body epithelium, retinal blood vessel endothelium, and retinal-pigmented epithelium, influence the overall amount of drug entering the anterior and posterior compartments of the eye from blood. As the blood-retinal barrier presents a greater hindrance to drug penetration than does the blood-aqueous barrier, the aqueous humor concentrations are typically higher than vitreous humor concentrations following systemic administration of drugs (Lesar and Fiscella, 1985). Periocular injections such as subconjunctival injections and intravitreal injections place drug more proximal to the target tissues, thereby overcoming some of the ocular barriers. In this section, physiochemical factors that affect the transport across blood-ocular barriers and case reports of drug transport are presented.
Ocular tissue permeability following topical administration can be influenced by the physicochemical properties of the drug. Molecular size restricts paracellular transport in cornea, conjunctiva, and sclera. The para-cellular and aqueous penetration routes in cornea, conjunctiva, and sclera were characterized in rabbits using a mixture of polyethyleneglycols (PEGs) with mean molecular weights of 200, 400, 600, and 1000, which display some basic features of peptides and oligonucleotides (hydrophilicity, hydrogen-
bonding capacity, and size) (Hamalainen et al., 1997). The conjunctival and scleral tissues were more permeable to PEGs than the cornea. The conjunc-tival permeability was less influenced by molecular size compared to that of cornea, which is expected because the conjunctiva has 2 times larger pores and 16 times higher pore density than the cornea. The total paracellular space in the conjunctiva was estimated to be 230 times greater than that in the cornea. Conjunctiva is commensurately permeable to hydrophilic molecules up to ~40 kDa. Prausnitiz and Noonan (1998) summarized the corneal, conjunctival, and scleral penetration of various drugs as a function of lipophilicity, molecular size, molecular radius, partition coefficient, and distribution coefficient. They observed an increase in corneal as well as corneal endothelial permeability with an increase in the drug distribution coefficient. Cornea as well as corneal endothelium exhibited molecular size-dependent drug permeability. Conjunctiva did not show clear dependence on distribution coefficient, but it did show a possible dependence on molecular size. Scleral transport was not dependent on either molecular radius or distribution coefficient.
Size is one determinant that influences the transport of molecules across blood-ocular barriers (Bellhorn, 1981). In a systematic study, the permeability of the ocular blood vessels and neuroepithelial layers in neonatal and adult cats was assessed using FITC-dextrans of various sizes. The iris and ciliary vessels were permeable to molecules with effective diffusion radius as large as 85 A. The choriocapillaries were permeable to molecules with an effective diffusion radius of 32-58 A. Iris vessels in humans, monkey, rabbit, and rat were not permeable to free and protein-bound sodium fluorescein, whereas marked permeability was observed in cats (Sherman et al, 1978).
Conjunctiva expresses organic cation transport processes (Ueda et al., 2000). The permeability of guanidine and tetramethylammonium in the mucosal-to-serosal direction was temperature and concentration dependent, and it was much greater than that in the serosal-to-mucosal direction. Guanidine transport was also inhibited by dipivefrine (72%), brimonidine (70%), and carbachol (78%). Also, acidification of mucosal fluid, apical exposure of a K+ ionophore, as well as high K+ levels reduced the transport of guanidine. However, it was not affected by the serosal presence of 0.5 mM ouabain. These observations suggest that transport of certain amine-type ophthalmic drugs may be driven by an inside-negative apical membrane potential difference.
Propranolol transport was assessed in conjunctival epithelial cells in the presence and absence of P-gp-competing substrates and anti-P-gp monoclonal antibody or a metabolic inhibitor, 2,4-DNP (Yang et al., 2000). Propranolol was transported preferentially in the basolateral-to-api-
cal direction. When exposed apically, inhibitors of P-gp, cyclosporin A, progesterone, rhodamine 123, verapamil, and 2,4-DNP increased propranolol accumulation by 43-66%. These results suggest that P-gp is likely localized on the apical plasma membrane to restrict the conjunctival absorption of some lipophilic drugs.
Cornea, conjunctiva, RPE, and iris pigment epithelial cells exhibit particulate uptake processes (Mayerson and Hall, 1986; Zimmer et al., 1991; Rezai et al., 1997). Zimmer et al. (1991) determined the uptake of 120 nm particles in excised rabbit cornea and conjunctiva. Following 30 minutes of incubation of rhodamine 6G nanoparticle suspension, particle uptake was observed in both tissues. No particles were observed in intercellular junctions probably because the openings for the intercellular space are too small for the 120 nm particles. Also, penetration of fluorescein was not seen in these cells or across the whole cornea when fluorescein solution instead of particles were used, suggesting the superiority of nanoparticles as a drug delivery system. Penetration through whole corneal tissue did not occur either. RPE cells possess nonspecific phagocytic activity and are capable of binding and ingesting latex particles (Mayerson and Hall, 1986; Aukunuru and Kompella, 1999b, 2002). Also, rod outer segments enter RPE via phagocytosis, which involves recognition, attachment, internalization, and degradation of the rod outer segments. With respect to particle uptake, iris pigment epithelial cells are functionally similar to RPE cells (Rezai et al., 1997).
Another important factor that may limit the ocular concentrations of some classes of drugs is the presence of an active transport system that removes drugs from ocular compartments and drains into blood. Barza et al. (1982) determined the kinetics of intravitreally injected carbenicillin, an organic anion antimicrobial, in rabbits following concomitant intraperito-neal administration of probenecid, an organic anion transport inhibitor. Probenecid increased the vitreous half-life of carbenicillin from 5 to 13 hours. In addition, it increased the drug concentrations in cornea, aqueous, and iris. Similar observations were made in rhesus monkeys, wherein pro-benecid increased the vitreous half-life of carbenicillin and cefazolin from 10 to 20 hours and 7 to 30 hours, respectively (Barza et al., 1983). These findings suggest that a probenecid-sensitive active transport system present in the retinal pigmented epithelium may actively remove organic acids such as penicillins and cephalosporins. Lipid-soluble compounds are also lost through the retina due to their ability to cross the blood-retinal barrier (Barza et al., 1982, 1983). Confounding ocular inflammation results in elimination of nontransported drugs such as aminoglycosides (Barza et al., 1983). However, the effect of inflammation on the loss of actively transported carbenicillin from the vitreous is less due to a decrease in the function of the active transport systems (Lesar and Fiscalle, 1985).
From the drug delivery point of view, monocarboxylate transport processes such as proton or Na + -coupled lactate systems in epithelial cells may serve as conduits for anionic drugs such as cromolyn, which is used in the treatment of vernal conjunctivitis and flurbiprofen and dicolfenac, which are used in the treatment of herpes conjunctivitis. Evidence exists for a Na + -dependent carrier-mediated monocarboxylate transport process on the mucosal side of the conjunctival epithelium (Horibe et al., 1998). This process may be used by ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) and fluoroquinolone antibacterial drugs. While NSAIDs and fluoroquinolones reduced L-lactate transport across conjunctiva, cromolyn and prostaglandins (PGE2 and PGF2) did not affect L-lactate transport, probably because cromolyn is a dicarboxylic acid and the hydrophobicity of PGE2 and PGF2 may hamper their recognition by the monocarboxylate transporter (Nord et al., 1983).
Besides Na + -lactate transporter, various ion transport processes discussed in Sec. III are likely to influence drug transport. The various ion transport processes can influence cell surface pH, fluid transport, tight junc-tional permeability, and vesicular trafficking, thereby altering drug transport (Kompella and Lee, 1999). Active transport of ions such as Na+, K + , and CP contributes to net fluid transport across various epithelia. For instance, cornea and conjunctiva secrete CP towards tears. In association with this CP secretion, net fluid secretion occurs towards tears. A change in this fluid secretion is likely to affect the transport of hydrophilic solutes. Exposure of nutrients such as amino acids to the apical side of conjunctiva can induce Na+ absorption in association with fluid absorption. This fluid absorption in conjunction with possible opening of tight junctions by these amino acids can allow increased absorption of hydrophilic solutes across conjunctiva. Elevation of intracellular Ca2+ through various transporters such as Ca2 + channels and Na + /Ca2+ exchanger is another likely approach to increase paracellular permeability. Function of CP channels such as CFTR correlate with the extent of endocytosis in various cells. Activation of CP channels with 8Br-cAMP and terbutaline have been shown to increase the transport of horseradish peroxidase (Kompella and Lee, 1999).
pH in the microclimate of the cell surface can be different from that in the surrounding fluid bulk. This is due to unstirred water layers and the presence of several surface transporters such as Na + /H+ exchanger, Na + / HCO^ cotransporter, and CP/HCO^ exchangers. Because transcellular diffusion of drugs is dependent on partitioning, which is dependent on pH, the function of these transporters is likely to influence drug transport. Indeed, inhibition of Na + /H+ exchanger with hexamethylene amiloride has been shown to elevate drug transport across conjunctiva (Kompella and Lee, 1999).
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