Drug Tissue Distribution of TUDCA From a Biodegradable Suprachoroidal Implant versus Intravitreal or Systemic Delivery in the Pig Model

Abstract

To determine local ocular tissue levels of the bile acid, tauroursodeoxycholic acid (TUDCA), in the pig model using oral, intravenous (IV), intravitreal injection (IVitI) and low-and high-dose suprachoroidal, sustained-release implants (SCI-L or SCI-H). Methods: Forty-six pigs (92 globes) were included in the study. TUDCA was delivered orally in 5 pigs, IV in 4, IVitI in 6, SCI-L in 17, and SCI-H in 14. Testing timeframes varied from the same day (within minutes) for IV; 1 to 6 days, oral; and 1 to 4 weeks, IVitI and SCI. Enucleated globes were dissected, specimens from specific tissues were separated, and TUDCA was extracted and quantified using mass spectrometry. Results: The highest TUDCA tissue levels occurred after IV delivery in the macula (252 ± 238 nM) and peripheral retina (196 ± 171 nM). Macular choroid and peripheral choroid levels were also high (1032 ± 1269 and 1219 ± 1486 nM, respectively). For IVitI delivery, macular levels at day 6 were low (0.5 ± 0.5 nM), whereas peripheral choroid was higher (15.3 ± 16.7 nM). Neither the SCI-L nor SCI-H implants delivered meaningful macular doses (≤1 nM); however, peripheral retina and choroid levels were significantly higher. Bile acid isoforms were found in the serum specimens. Conclusions: The highest TUDCA tissue levels in the pig model were obtained using IV delivery. Oral delivery was associated with reasonable tissue levels. Local delivery (IVitI and SCI) was able to achieve measurable local ocular tissue levels. Translational Relevance: Diffusional kinetics from the suprachoroidal space follow the choroidal blood flow, away from the macula and toward the periphery.

Genome editing in the treatment of ocular diseases

“…Suprachoroidal injection can promote panretinal delivery and sustained administration of therapeutic agents or genetic material more easily than subretinal injection 195 . However, there are challenges to delivering therapeutic agents from the suprachoroidal space to the retina because of Bruch’s membrane and the RPE 196 . Suprachoroidal injection of triamcinolone acetonide (TA), a glucocorticoid agonist is enormously successful in delivering steroid to the retina.…”

Suprachoroidal Delivery of Small Molecules, Nanoparticles, Gene and Cell Therapies for Ocular Diseases

“…Furthermore, tauroursodeoxycholic acid (TUDCA), a potential neuroprotective agent, has been evaluated when administered suprachoroidally [ 69 , 70 ]. Olsen et al loaded polycaprolactone-polyethylene glycol polymer with TUDCA and implanted it into the SCS or the vitreous humor (IVT) in pigs [ 71 ]. In in vitro drug release assays, a rapid burst of TUDCA from the implant surface was observed, followed by a slower, sustained release through diffusion.…”