access to periocular space and could potentially diffuse across the posterior sclera to the retina. Drug administered in this manner showed very low levels in the aqueous humor, and suggests corneal permeability is required for significant aqueous humor concentrations.

5.2.2  Studies of Trans-Corneal and Periocular Drug Delivery to the Retina

The periocular route: Several studies on beta-adrenergic receptor blockers (e.g., Propranolol, Atenolol, Timolol, and Nipradilol) provide insight on the transit of drug from ophthalmic drops to the retina. In the case of Timolol, restricting the application of a 14C radiolabeled derivative to the corneal surface using the Patton chamber led to rapid penetration across the corneal epithelium and accumulation in the aqueous humor. This did not result in therapeutically significant levels of Timolol in either the vitreous or posterior segments, indicating that neither the trans-vitreous nor the uvea-scleral trans-corneal routes were significant for Timolol. However, drug applied on the conjunctiva was shown to rapidly diffuse across the conjunctiva to gain access to periocular fluid and the posterior sclera. Timolol levels in the cornea and aqueous humor were significantly less when the drug solution was denied contact with the cornea surface. These results support the periocular trans-scleral route as the predominant route for Timilol transit to the back of the eye, and that drug distribution via this path can be rapid.

More recently, in a study in rabbits using both radiolabeled and unlabeled drug, the distribution of Nipradilol (an analog of Atenolol, Propanalol, and Timolol) was studied following administration as an ophthalmic drop, sub-tenon injection and an injection into the aqueous humor (Mizuno et al. 2009). With the ophthalmic drop, drug rapidly appeared at high levels in the cornea, conjunctiva, and aqueous humor compartments. Drug also rapidly distributed at lower levels into periocular tissues encompassing the entire eye, and appeared in retinal/choridal tissues at levels >100 nM within 20–60 min; however, it was undetectable in the vitreous at these time points. This drug distribution pattern excludes trans-vitreous uptake into the posterior tissues. In addition, the drug injected into the aqueous humor remained at high levels in the anterior chamber and cornea, but did not distribute into the posterior vitreous or retinal space, and thus discounts the uvea-scleral route of distribution of Nipradilol to these compartments. Drug from the sub-tenon injection did appear at significant levels in the retinal/choroidal space but was below the limit of detection in the vitreous, anterior chamber, and cornea. Consequently, it appears that while Nipradilol reaches the cornea and anterior chamber via the trans-corneal route, it reaches posterior retinal tissues via the periocular trans-scleral route.

The trans-vitreous route: This route has proven difficult to separate from the periocular route demonstrated for the beta blockers noted above. No clear data exists for a study with the use of the Patton chamber to assure corneal dosing.

Brimonidine is an a2-adrenergic agonist for the treatment of both the intraocular pressure and neurodegenerative aspects of glaucoma. Brimonidine has been detected

in the tissues of the anterior and posterior segments following administration of an ophthalmic drop to the anterior ocular surface (Table 5.2). In monkeys and rabbits dosed with 14C-labeled drug, high levels are achieved in the choroid/retina after single or multiple doses (Acheampong et al. 2002). Systemic drug levels resulting from topically applied drug were low compared to ocular tissue levels in both species. In addition, drug levels in the treated eye were significantly higher than that in the untreated eye in rabbits (Cmax vitreous: 49.3 vs. 2.0 nM). These data are suggestive of a local route of transit of Brimodine to posterior tissues. Pharmacokinetic analysis indicates that the drug reaches its maximum concentration first at the ocular surface and aqueous humor, followed by the vitreous and finally the retina/choroid. This is consistent with a trans-vitreous trans-corneal delivery of drug to the retina via an ophthalmic drop. While drug concentrations follow the anticipated concentration gradient from corneal surface to aqueous humor and vitreous, the tissue levels of Brimonidine in the retina/choroid are more than ten times higher than in the vitreous. This is inconsistent with a trans-vitreous trans-corneal uptake but may result from high levels of melanin binding in the pigmented retinal/choroidal tissues or a periocular trans-scleral distribution route. Studies in humans undergoing an elective vitrectomy reveal drug levels in the vitreous were similar to that seen in monkeys (Kent et al. 2001). Levels in the vitreous of aphakic patients were noted to be significantly higher than normal subjects and may indicate that the lens is a significant barrier to trans-vitreous trans-corneal distribution of drug to the retina.

A recent study in rats using high concentrations (i.e., 0.1 M) of a 14C-labeled immunomodulator SAR 1118 demonstrated both a concentration gradient across tissues from the ocular surface through the aqueous and vitreous compartments to the retina/choroid and concentration time profile consistent with a trans-vitreous trans-corneal route of delivery to the retina (Rao et al. 2010).

5.2.2.1  The Uvea-Scleral Route

Studies with radiolabeled albumin injected into the anterior segment of a cynomo­ logous monkey demonstrated that the uvea-scleral outflow of the contents of the aqueous humor can be enhanced by modulation of the ciliary muscles with topical application of the prostaglandin PGF2a-1 isopropyl ester. Radiolabeled albumin appeared in the suprachoroidal space and transited to the ocular posterior pole within 2 h of administration (Stjernschantz et al. 1999; Alm and Nilsson 2009). Similar results have been observed in aged human eyes scheduled for enucleation (Bill and Phillips 1971). It has been suggested that prostaglandins secreted in