Sustained reduction of intraocular pressure by supraciliary delivery of brimonidine-loaded poly(lactic acid) microspheres for the treatment of glaucoma

Abstract

Although effective drugs that lower intraocular pressure (IOP) in the management of glaucoma exist, their efficacy is limited by poor patient adherence to the prescribed eye drop regimen. To replace the need for eye drops, in this study we tested the hypothesis that IOP can be reduced for one month after a single targeted injection using a microneedle for administration of a glaucoma medication (i.e., brimonidine) formulated for sustained release in the supraciliary space of the eye adjacent to the drug’s site of action at the ciliary body. To test this hypothesis, brimonidine-loaded microspheres were formulated using poly(lactic acid) (PLA) to release brimonidine at a constant rate for 35 days and microneedles were designed to penetrate through the sclera, without penetrating into the choroid/retina, in order to target injection into the supraciliary space. A single administration of these microspheres using a hollow microneedle was performed in the eye of New Zealand White rabbits and was found to reduce IOP initially by 6 mm Hg and then by progressively smaller amounts for more than one month. All administrations were well tolerated without significant adverse events, although histological examination showed a foreign-body reaction to the microspheres. This study demonstrates, for the first time, that the highly-targeted delivery of brimonidine-loaded microspheres into the supraciliary space using a microneedle is able to reduce IOP for one month as an alternative to daily eye drops.

Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection

“…Compared with these conventional routes of administration, SCS delivery enables targeted drug delivery to the choroid, retina, ciliary body, and sclera with higher bioavailability (Chiang et al, 2016a; Kim et al, 2014b; Olsen et al, 2011; Patel et al, 2012; Patel et al, 2011; Wang et al, 2012), and can be performed in the outpatient clinic setting (Goldstein, 2015; Patel et al, 2012; Patel et al, 2011). The extent and distribution of posterior-segment diseases are typically not uniform.…”

“…The extent and distribution of posterior-segment diseases are typically not uniform. For example, glaucoma treatment requires localization near the ciliary body, which is near the site of microneedle injection (Chiang et al, 2016a; Kim et al, 2014b); while noninfectious posterior uveitis requires spreading throughout the SCS (Goldstein, 2015). Deposition within the SCS can be geographically controlled so as to target diseased tissues while sparing non-diseased tissues (Chiang et al, 2016b; Einmahl et al, 2002; Kim et al, 2014a; Kim et al, 2015; Tyagi et al, 2013).…”

“…However, the use of particles (e.g., containing drug molecules for slow release over time (Chiang et al, 2016a; Goldstein, 2015)) may be preferable to injecting free drug molecules, which are usually cleared from the SCS within a day (Gu et al, 2015; Kim et al, 2014b; Olsen et al, 2011; Patel et al, 2012). …”

“…It was previously shown that molecules injected in HBSS were cleared from the SCS within hours-days (Gu et al, 2015; Olsen et al, 2011; Wang et al, 2012), whereas particles appear not to be cleared at all (Chen et al, 2015; Chiang et al, 2016a; Kim et al, 2015; Patel et al, 2012; Patel et al, 2011). Here, we show that at 3 min and 1 h, fluorescein spread more than particles and that particles co-localized in the SCS with fluorescein only at 3 min.…”

“…In some cases, it is desirable to have drug distributed over a large area of the SCS to broadly deliver drug to the chorioretina (e.g., to treat posterior uveitis (Goldstein, 2015)). In other cases, it may be desirable to localize the drug near the site of injection (e.g., to treat glaucoma)(Chiang et al, 2016a; Kim et al, 2014b). …”