Biomechanics of suprachoroidal drug delivery: From benchtop to clinical investigation in ocular therapies

Figures & data

Figure 1. Cross-sectional anatomy illustration of the human eye. The suprachoroidal space (SCS) is denoted in yellow and is occluded anteriorly by the scleral spur, as seen in the magnified region of the illustration. Image updated from https://www.scientificanimations.com, CC BY-SA 4.0, via Wikimedia Commons

Figure 2. Suprachoroidally injected fluorescing dye under UV light in an ex vivo porcine eye before (A), during (B), and immediately post (C) injection shows posterior and circumferential spread of the injectate within the suprachoroidal space (SCS), as seen by the fluorescing particles emitting light through the scleral tissue. (D) is a diagram of a partial cross-section of an eye with suprachoroidally injected fluid spreading posteriorly and circumferentially between the sclera and choroid around the globe

Table 1. Formula and procedure optimization properties, and the relationship they have on key aspects of suprachoroidal delivery, including sustained pharmacokinetic effect, targeting of the posterior pole, and circumferential distribution

		Effect on suprachoroidal delivery
	Property	Sustained Pharmacokinetic Effect	Target Posterior Pole	Circumferential Distribution
Formulation Optimization	Increased Viscosity	+[36]		-[40]
	Non-Newtonian Fluid	+[40]		-[40]
	Volume Injected	+[27,36]	+[27,36]	+[27,36]
	Increased Particle Size	+[29,42,43]
	High Drug Particle Solubility	-[42]		+[41]
Procedure Optimization	Hydrogel Pushing		+[46]
	Multi-quadrant Injection			+[38]
	Iontophoresis		+[47,48]

‘+’ denotes potential positive impact. ‘-’ denotes potential negative impact

Table 2. Clinical trials involving suprachoroidal injections of an investigational formulation of triamcinolone acetonide (CLS-TA)

	Study
	TANZANITE	SAPPHIRE	TOPAZ	DOGWOOD	PEACHTREE	AZALEA	MAGNOLIA	HULK	TYBEE
ClinicalTrials.gov Identifier	NCT02303184	NCT02980874	NCT03203447	NCT02255032	NCT02595398	NCT03097315	NCT02952001	NCT02949024	NCT03126786
Study Title	Safety and Efficacy of Suprachoroidal CLS-TA in Combination With Intravitreal Aflibercept in Subjects With Macular Edema Following Retinal Vein Occlusion	A Randomized, Masked, Controlled Trial To Study The Safety And Efficacy Of Suprachoroidal CLS-TA In Conjunction With Intravitreal Aflibercept In Subjects With Retinal Vein Occlusion	A Randomized, Masked, Controlled Trial to Study the Safety and Efficacy of Suprachoroidal CLS-TA in Combination with an Intravitreal anti-VEGF Agent in Subjects with Retinal Vein Occlusion	A Randomized, Masked, multicenter study to assess the safety and efficacy of CLS-TA, triamcinolone acetonide injectable suspension in the treatment of subjects with macular edema following uveitis	A Phase 3, randomized, masked, controlled clinical trial to study the safety and efficacy of triamcinolone acetonide injectable suspension (CLS-TA) for the treatment of subjects with macular edema associated with noninfectious uveitis	Open-label safety study of suprachoroidal triamcinolone acetonide injectable suspension in patients with noninfectious uveitis	Multi-Center, Non-Interventional Extension Study of the Safety and Efficacy of CLS-TA for the Treatment of Macular Edema Associated With Noninfectious Uveitis	Open-Label Study of the Safety and Efficacy of Suprachoroidal CLS-TA Alone or in Combination With Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema	Randomized, Double Masked, Controlled Study Comparing the Safety and Efficacy of Suprachoroidal CLS-TA With Intravitreal Aflibercept Versus Aflibercept Alone in Subject With Diabetic Macular Edema
Disease State	RVO	RVO	RVO	NIU	NIU	NIU	NIU	DME	DME
Phase	2	3	3	2	3	3	Extension Study	1/2	2
Duration	12 weeks	48 weeks	48 weeks	8 weeks	24 weeks	24 weeks	24 weeks	24 weeks	24 weeks
Study Design	Randomized, double-masked, multicenter	Randomized, double-masked, multicenter	Randomized, double-masked, multicenter	Randomized, double-masked, multicenter	Randomized, double-masked, multicenter	Open-label, multicenter	Observational	Open-label, multicenter	Randomized, double-masked, multicenter
Treatment(s)^1	Suprachoroidal CLS-TA 4 mg at week 0 with IVT anti-VEGF or sham suprachoroidal injection with IVT anti-VEGF	Suprachoroidal CLS-TA 4 mg at weeks 0, 12, 24 with IVT aflibercept or sham suprachoroidal injection with IVT aflibercept	Suprachoroidal CLS-TA 4 mg at weeks 0, 12, 24 with IVT anti-VEGF or sham suprachoroidal injection with IVT anti-VEGF	Suprachoroidal CLS-TA 0.8 mg or Suprachoroidal CLS-TA 4 mg	Suprachoroidal CLS-TA 4 mg at weeks 0 and 12 or sham suprachoroidal injection	Suprachoroidal CLS-TA 4 mg at weeks 0 and 12	None (non-interventional)	Suprachoroidal CLS-TA 4 mg or CLS-TA 4 mg with IVT aflibercept	Suprachoroidal CLS-TA 4 mg at weeks 0 and 12 with IVT aflibercept or sham suprachoroidal injection with IVT aflibercept

¹Patients were eligible for rescue at other visits as determined by predefined criteria.RVO: retinal vein occlusion; NIU: noninfectious uveitis; DME: diabetic macular edema; IVT: intravitreal

Chiang B, Venugopal N, Grossniklaus HE, et al. Thickness and closure kinetics of the suprachoroidal space following microneedle injection of liquid formulations. Invest Ophthalmol Vis Sci. 2017;58(1):555–564.

 PubMed Web of Science ®Google Scholar

Kim YC, Oh KH, Edelhauser HF, et al. Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles. Eur J Pharm Biopharm. 2015 Sep;95(Pt B):398–406.

 PubMed Web of Science ®Google Scholar

Chiang B, Kim YC, Edelhauser HF, et al. Circumferential flow of particles in the suprachoroidal space is impeded by the posterior ciliary arteries. Exp Eye Res. 2016;145:424–431.

 PubMed Web of Science ®Google Scholar

Patel SR, Lin AS, Edelhauser HF, et al. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm Res. 2011 Jan;28(1):166–176.

 PubMed Web of Science ®Google Scholar

Hackett SF, Fu J, Kim YC, et al. Sustained delivery of acriflavine from the suprachoroidal space provides long term suppression of choroidal neovascularization. Biomaterials. 2020;243:119935.

 PubMed Web of Science ®Google Scholar

Chiang B, Wang K, Ethier CR, et al. Clearance kinetics and clearance routes of molecules from the suprachoroidal space after microneedle injection. Invest Ophthalmol Vis Sci. 2017;58(1):545–554.

 PubMed Web of Science ®Google Scholar

Chiang B, Venugopal N, Edelhauser HF, et al. Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection. Exp Eye Res. 2016;153:101–109.

 PubMed Web of Science ®Google Scholar

Jung JH, Desit P, Prausnitz MR. Targeted drug delivery in the suprachoroidal space by swollen hydrogel pushing. Invest Ophthalmol Vis Sci. 2018;59(5):2069–2079.

 PubMed Web of Science ®Google Scholar

Nork TM, Katz AW, Kim CBY, et al. Distribution of aqueous solutions injected suprachoroidally (SC) in rabbits. Invest Ophthalmol Vis Sci. 2020;61(7):320.

 Web of Science ®Google Scholar

Jung JH, Chiang B, Grossniklaus HE, et al. Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle. J Control Release. 2018 May;10(277):14–22.

 Web of Science ®Google Scholar

Touchard E, Berdugo M, Bigey P, et al. Suprachoroidal electrotransfer: a nonviral gene delivery method to transfect the choroid and the retina without detaching the retina. Mol Ther. 2012;20(8):1559–1570.

 PubMed Web of Science ®Google Scholar