As previously mentioned in this chapter, while there is some evidence for direct drug delivery via the topical ocular route, drugs usually do not reach therapeutically relevant levels in the posterior segment following topical ocular instillation. If significant concentrations are achieved at the back of the eye, they are usually the result of redistribution from the systemic circulation, not local delivery. Consequently, to treat diseases of the posterior segment, drug must typically be administered intravitreally, periocularly, or systemically. Systemic administration will be discussed later in this chapter. Intravitreal injection has been discussed and is quite effective but, as has been mentioned, presents a serious risk to the eye. Periocular drug administration, using subconjunctival, sub-Tenon's, or retrobulbar injection, is
another and, in many cases, preferred, route for delivering drugs to the posterior segment (59).
Subconjunctival injection offers the advantage of local drug delivery without the invasiveness of intravitreal injection. This route also allows for the use of drug depots to prolong the duration of drug therapy and avoids much of the toxicity encountered with systemic administration. Drug concentrations in the eye are typically substantially higher following subconjunctival versus systemic administration, while systemic exposure is greatly reduced with subconjunctival dosing. For example, following subconjunctival injection of 6-mercatopurine, mean peak concentrations in aqueous and vitreous were 15 and 10 times those following intravenous administration, while serum levels were about half (85). In another example, rabbits were administered 14C-5-fluorouracil either subconjunctivally or intravenously (86). Peak levels of parent in the serum and urine were similar for the two routes; however, subconjunc-tival injection resulted in peak aqueous concentrations of 125 and 380 times that after intravenous injectiotn. The localized deliver of hydrocortisone by the subconjunctival route has been demonstrated by McCartney et al. in the rabbit eye (87). Their results showed that hydrocortisone penetrated directly into the eye with minimal spread beyond the site of administration.
Various studies have explored the mechanism by which drugs are absorbed into the eye following subconjunctival administration. Maurice and Mishima point to direct penetration to deeper tissues as the main pathway of entry into the anterior chamber (4). A necessary first condition, however, is the saturation of the underlying sclera with drug. This is followed by diffusion by various possible routes: laterally into corneal stroma and across the endothelium, across trabecular mesh-work, through the iris stroma and across its anterior surface, into the ciliary body stroma and into newly generated aqueous humor, and into the vitreous body via the pars plana and across its anterior hyloid membrane (4). In addition to these pathways, depending on the injection volume, regurgitation out the dose site with subsequent spillage onto the cornea can lead to direct transcorneal absorption. For example, Conrad and Robinson investigated the mechanism of subcon-junctival drug delivery using pilocarpine nitrate, albino rabbits, and instillation volumes ranging from 60 to 500 mL (88). At high injection volumes (>200 mL), the primary mechanism for uptake into the aqueous was reflux of the drug solution from the injection site followed by corneal absorption. At lower volumes, the mechanism involved reflux and transconjunctival penetration, permeation of the globe, and systemic absorption followed by redistribution.
2. Periocular Injection (Sub-Tenon's and Retrobulbar)
Sub-Tenon's injection involves delivery of drug, usually as a depot, between the sub-Tenon's capsule and sclera or episclera. This route of administration has the advantage of placing drug in very close proximity to the sclera. Drug can subsequently diffuse through the sclera, which is quite permeable to a wide range of molecular weight compounds (59,89). Because the diffusion of drug from the dose site can be very localized, the preferred location of dose is directly over the target. For example, Freeman et al. performed localization of sub-Tenon's repository injection of corticosteroid (90). Echography showed drug within the sub-Tenon's space over the macula in 11 of 24 cases. The lack of therapeutic response to repository steroids was attributed to placement relative to target.
Except for the observation that bleb retrobulbar injection spreads forward, unlike subconjunctival injection which spreads backward, these two injection routes yield very similar results. Bodker et al. compared ocular tissue levels of dexamethasone 1 and 4 hours after subconjunctival or retrobulbar injection in rabbits (91). In both dosage route groups, concentrations in all three tissues (aqueous, vitreous, retina) were similar 1 hour postdose. After 4 hours, levels in the two groups were again similar except in choroid. Dosed and contralateral undosed eye tissues contained similar levels after 4 hours with the exception of retina, which had lower levels in undosed eye versus dosed. Retrobulbar dosing, however, provided a more sustained drug delivery than with subconjunc-tival administration.
Retrobulbar (or peribulbar) injection is another option for delivering drug to the posterior segment and the vitreous. Hyndiuk and Reagan determined the penetration and persistence of retrobulbar depot-corticosteroid in monkey ocular tissues (92). High concentrations were found in posterior uvea with persistence of lower concentrations. Steroid tended to concentrate in the optic nerve after retrobulbar but not systemic administration, and no drug was detected in other ocular tissues with the exception of lens and vitreous after 2 and 9 days. Weijten et al. studied the penetration of dex-amethasone into the human vitreous and its systemic uptake following peri-bulbar injection (93). Mean levels in the vitreous peaked at 13 ng/mL at 6-7 hours postdose, and maximal serum level was 60 ng/mL 20-30 minutes postdose.
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