DESIGN OF DRUG DELIVERY SYSTEMS TARGETING THE NONCORNEAL ROUTE

V. DESIGN OF DRUG DELIVERY SYSTEMS TARGETING THE NONCORNEAL ROUTE

There are limited reports of practical examples of noncorneal drug delivery dosage forms and drug delivery systems. As noted previously, the noncor- neal pathway may be best suited to deliver large, polar molecules, which have poor permeability across the cornea and which are less likely to be extensively cleared by systemic loss via absorption into the ocular blood vessels. However, effective noncorneal drug delivery is likely to require spe- cial considerations in dosage form design and methods of administration that can minimize precorneal and retain high concentrations of drug at the absorptive surfaces or the conjunctiva or sclera. Delivery system options may include bioadhesive polymeric vehicles, controlled release inserts, pro- drugs, microparticulates, and scleral implants. The method of administra- tion that is most likely to maximize the opportunity to deliver drugs via the noncorneal route is suprachoroidal delivery via subconjunctival or sub- Tenon’s injection or implantation, as these methods are best suited to administer the drug in close proximity of the absorbing surface as a depot form. Iontophoretic delivery is an option that has not yet been explored for noncorneal deliver, as is the approach of minimizing systemic drug loss via absorption into the conjunctival blood vessels by using vasoconstrictors.

A. Custom Vehicles Romanelli et al. (20) studied the absorption, distribution, and elimination of

bendazac in ocular tissues after topical administration as eye drops formu- lated with different polysaccharide vehicles. Based on spatial and temporal distribution of drug in ocular tissues, they concluded that bendazac entered

352 Ahmed the retina-choroid and the iris-ciliary body by a sclero-conjunctival route.

Lehr et al. (21) investigated the use of polycarbophil, a mucoadhesive poly- mer, to improve the ocular delivery of gentamicin formulated in eye drops.

A twofold increase in bulbar conjunctival levels was noted. Based on the rank-order of peak concentrations and peak times in ocular tissues, the authors proposed that gentamicin formulated in polycarbophil-containing eyedrops reach the anterior chamber primarily via the noncorneal route.

B. Conjunctival Inserts Urtti et al. (7) showed that application site–dependent absorption of timolol

formulated in a silicone cylindrical device that released drug at 7.2 m/h. Very low timolol concentrations in the aqueous humor following placement of the device in the inferior conjunctival sac and high drug concentrations in parts of each tissue that was closer to the site of application was presented as evidence of noncorneal entry.

C. Microparticulates Ahmed et al. (23) showed evidence of site-specific, noncorneal delivery of

inulin to the posterior eye from topical application of multilamellar lipo- somes. It is reasonable to expect that noncorneal delivery of some drugs using nanoparticulates may be feasible.

D. Prodrugs and Enhancers In a preliminary evaluation of a series of amphiphilic timolol prodrugs, Pech

et al. (18) presented possible evidence of transscleral absorption. The poten- tial of a drug latentiation as a means to promote selective noncorneal entry was also presented in the in vitro evaluation of polyethylene glycol esters of hydrocortisone 21-succinate as ocular prodrugs (120). Chien et al. reported

improved permeability across the conjunctiva for prostaglandin F 2a pro- drugs (19). Noncorneal enhancers may be agents that reduce systemic loss or increase conjunctival permeability. Epinephrine pretreatment did not significantly affect the concentrations of topically applied timolol in the cornea, aqueous humor, iris-ciliary body, and conjunctiva of rabbits but resulted in significantly higher concentrations in the sclera (67). Although not explicitly stated, this approach of minimizing systemic loss with vaso- constrictors may render noncorneal entry of selective drugs more favorable. There have been some exciting leads in approaches and entities to transi- ently enhance the epithelial permeability of ocular membranes (122–124). The technology of enhancing the conjunctival permeability may become available in the near future.

The Noncorneal Route in Ocular Drug Delivery 353

E. Devices and Novel Administration Methods Arguably the most promising approach to noncorneal delivery is deposition

of drug, preferably as a depot or as a biodegradable implant at, or in the near proximity of the episclera. Kunou et al. (119) formulated betametha- sone phosphate in a biodegradable, polylactic glycolic acid scleral implant and showed that the drug concentrations in the retina-choroid stayed in the therapeutic range for one month. Further, the concentrations in the retina- choroid were consistently greater than in the vitreous, which is evidence of noncorneal entry. Transcleral penetration of drugs following subconjuncti- val and sub-Tenon’s injection is precedented and is considered to be a viable approach for delivering drugs to the posterior tissues of the eye (125–127). Advances in iontophoretic techniques present the possibility that trans- scleral iontophoresis may replace or supplement intravitreal injection of antibiotics for the treatment of endophthalmitis (128–130).

VI. CONCLUSIONS/FUTURE DIRECTION Based on the current understanding it is possible to put the conjunctival/

scleral pathway for intraocular entry of drugs in perspective vis-a-vis ocular drug delivery. First, the noncorneal penetration pathway involves the per- meation of drug across the conjunctiva and sclera and may contribute sig- nificantly to drug penetration into intraocular tissues for some drugs. Second, drug entering the eye via the cornea enters the aqueous humor and provides high drug levels to the anterior segment tissues, as described earlier. In contrast, the fraction of drug entering the eye via the noncorneal route may bypass the anterior chamber and access tissues of the posterior segment of the eye, such as the uveal tract, choroid, and retina and, to a lesser extent, the vitreous humor. The differential spatial distribution of drug entering the eye via the corneal versus conjunctival/scleral pathway has exciting implications in terms of ocular drug delivery. For example, whereas the corneal route may be preferred for treating anterior segment eye disease (e.g., glaucoma), the noncorneal route may be considered for drug therapy targeting the posterior segment of the eye (e.g., uveitis, chor- oidal neovascular membrane formation, viral retinitis, age-related macular degeneration). Third, the nonproductive loss of ocularly applied drugs to the systemic circulation diminishes the fraction of drug that can enter the eye via the noncorneal route. Since the cornea is nonvascularized, the con- junctival/scleral entry is a minor pathway for most small, semipolar hetero- cycles that represent the majority of commonly used ophthalmic drugs. However, the noncorneal pathway may become significant for large, polar

354 Ahmed molecules, administration methods that can minimize precorneal and sys-

temic loss, drugs susceptible to degradation during diffusion across the cornea, and for delivery systems that can retain high concentrations of drug at the absorptive surfaces or the conjunctiva or sclera.

Recent advances in drug delivery systems that minimize precorneal loss and can retain high concentrations of drug at the absorptive surfaces of the conjunctiva or sclera may be particularly suited for noncorneal deliv- ery. These include bioadhesive vehicles, microparticulates, and controlled release conjunctival inserts. Suprachoroidal delivery of drugs via subcon- junctival and sub-Tenon’s injection, scleral and suprachoroidal implants, may be the most promising approach to noncorneal delivery. Prodrugs and permeation enhancers and vasoconstrictors are plausible concepts, but they require further investigation.

Much progress has been made over the past two decades towards understanding the fundamental basis of drug penetration via the noncorneal pathway. The challenge for the future is to creatively apply the available knowledge to the practical design of drugs and drug delivery systems for ocular therapy. Noncorneal delivery is not a panacea and will probably have niche utility in ocular drug delivery. The greatest potential for the concept appears to be in the area of intraocular delivery of polar molecules, peptides and protein drugs, and directed drug delivery to treat posterior segment eye disease.

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