Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles

Experimental Eye Research

Kim

Edelhauser

et al. 2016

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Microneedle injection into the suprachoroidal space (SCS) enables targeted drug delivery for treatment of posterior segment diseases (e.g., posterior uveitis). This study sought to identify and characterize anatomical barriers to circumferential spread of particles in the SCS of rabbit and human cadaver eyes. These barriers could make targeting specific regions within the SCS challenging. A hollow microneedle (33-gauge, 750 μm long) was used to inject fluorescent particles into albino New Zealand White rabbit eyes ex vivo at six different positions around the limbus and a limited number of conditions in vivo. SCS injections were also performed in human cadaver eyes 8 mm and 2 mm from the optic nerve (ON). Eyes were dissected and particle distribution was quantified. In rabbit eyes, injections made in the superior or inferior hemispheres (even when injected temporally immediately adjacent to the long posterior ciliary artery (LPCA)) did not significantly cross into the other hemisphere, apparently due to a barrier formed by the LPCA. The vortex veins had a minor effect on particle deposition, limited to only around the vortex vein root. In human eyes, the short posterior ciliary arteries (SPCAs) prevented circumferential spread towards the macula and ON. In conclusion, the rabbit LPCA and the human SPCA were anatomical barriers to particle spread within the SCS. Therefore, design of drug delivery protocols targeting the SCS need to account for barriers formed by anatomical structures in order for injected drug to reach target tissues.

Section: Discussionmentioning

confidence: 86%

“…Previous studies using particles suspended in HBSS have indicated that particle spread occurs at the time of injection, after which the particles do not move (Kim et al, 2014b, c; Kim et al, 2015; Patel et al, 2012; Patel et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Circumferential flow of particles in the suprachoroidal space is impeded by the posterior ciliary arteries

Experimental Eye Research

Kim

Edelhauser

et al. 2016

Self Cite

“…2). We and others have seen that injection of larger volumes leads to spread over a larger area of the suprachoroidal space [41, 47–49]. To localize our formulation at the site of injection at the supraciliary space, we wanted to minimize the injection volume and therefore needed to give multiple injections in order to deliver the target dose.…”

Section: Resultsmentioning

confidence: 99%

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

Journal of Controlled Release

Kim

Doty

et al. 2016

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.

“…Previous studies have used the two-dimensional (2D) circumferential spread of particles injected into the SCS as the primary metric of distribution (Kim et al, 2014a, b; Kim et al, 2015; Patel et al, 2012; Patel et al, 2011). Though many studies have investigated the distribution of particles (Chen et al, 2015; Kim et al, 2014a; Kim et al, 2015; Patel et al, 2012; Patel et al, 2011) and molecules (Kim et al, 2014b; Olsen et al, 2011; Patel et al, 2012; Tyagi et al, 2013; Wang et al, 2012) independently, to our knowledge, no study has examined the distribution of particles and molecules injected into the SCS simultaneously, or imaged the distribution of polymeric formulation excipients in the SCS.…”

Section: Introductionmentioning

confidence: 99%

“…Though many studies have investigated the distribution of particles (Chen et al, 2015; Kim et al, 2014a; Kim et al, 2015; Patel et al, 2012; Patel et al, 2011) and molecules (Kim et al, 2014b; Olsen et al, 2011; Patel et al, 2012; Tyagi et al, 2013; Wang et al, 2012) independently, to our knowledge, no study has examined the distribution of particles and molecules injected into the SCS simultaneously, or imaged the distribution of polymeric formulation excipients in the SCS. Better understanding of how particles move relative to the formulation will enable the rational design of formulations that control particle spreading in the SCS.…”

Section: Introductionmentioning

confidence: 99%

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

Experimental Eye Research

Venugopal

Edelhauser

et al. 2016

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The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25–150 μL Hank’s Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02 – 2 μm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm – 2 μm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2 – 4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1 – 3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allow spreading over larger areas of the SCS until the particles and excipients dissociate.