title: Effect of intraocular pressure (IOP) and choroidal circulation on controlled episcleral drug delivery to retina/vitreous.
abstract: Transscleral drug delivery may become a safe alternative to the intravitreal injection for chronic retinal diseases such as age-related macular degeneration or diabetic macular edema. However, the drug delivered onto the sclera subjects to vigorous clearance by episcleral and choroidal circulation; in addition, the penetration from episclera to retina needs to overcome counter-directional ocular fluid current driven by intraocular pressure (IOP) as well as unfavorable drug disposition exerted by drug transporters before the drug reach retina. It is imperative to understand these processes and quantitate their influence for efficient designing of a sustained formulation or device to achieve efficient transscleral drug delivery. The current study was focused on the effects of intraocular pressure (IOP) and choroidal circulation on transscleral drug delivery using triamcinolone acetonide (TA) as a model drug. Rabbit eye IOP was modulated through cannulation in ex vivo study or through cryopexy of ciliary body in vivo studies before subtenon TA injection or episcleral TA-film implantation. In a subgroup of the rabbit eyes, localized choroid atrophy was induced by cryopexy before TA-film implantation. Each condition had a concurrent control group. The vitreous TA concentration was quantitated by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS). The vitreous TA concentration was compared between the study and control groups for effect of IOP or choroid circulation. For ex vivo studies, higher IOP was a significant effect against TA penetration from episclera towards vitreous. TA was 8.5±5ng/mL in receptor chamber with a cross pressure of 50mmHg versus 15.9±10ng/mL with the cross pressure of 5mmHg; p=0.001, t-test. A multivariate regression demonstrated each mmHg of IOP increase would result in 3ng/mL lower concentration in the receptor chamber. Similar IOP effect was also identified in a 3-hour study using euthanized rabbit eyes whose IOP was controlled at 10 or 40mmHg by cannulation (3261±1821ng/mL vs. 755±763ng/mL; p=0.013, Wilcoxon test). However, the effect of IOP was not significant in alive animal with the same IOP setting. In vivo chronic study using low IOP (7.7mmHg) versus normal IOP (14.4mmHg), vitreous TA was not statistically significant (154±200ng/mL vs. 80±130ng/mL, p=0.17, Wilcoxon test). However, removing of choroidal circulation by local cryopexy significantly enhanced the TA penetration from episclera to vitreous (mean 163±129.8ng/mL for choroidal cryopexy vs. 81.8±37.2ng/mL for ciliary cryopexy or 75.5±36ng/mL for control group, p=0.007, regression analysis). In conclusion, the effect of IOP on transscleral drug delivery was not a significant effect in alive rabbit eyes; however, choroidal circulation seems to be a significant effect to affect TA penetration from episclera towards retina and vitreous.
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; Department of Ophthalmology at Fuyang People's Hospital, Fuyang, Anhui 236000, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; Ningbo Eye Hospital, Ningbo, Zhejiang 315040, China.
authors.forename: Bifei
authors.initials: B
authors.lastname: Lan
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China.
authors.forename: Shumao
authors.initials: S
authors.lastname: Sun
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; Jacob's Retina Center at Shiley Eye Institute, Department of Ophthalmology, University of California San Diego, 9415 Campus Point Drive, La Jolla, CA 92037-0946, United States. Electronic address: l1cheng@ucsd.edu.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002829:Choroid / Q000098:blood supply; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D015195:Drug Design; D007429:Intraocular Pressure / Q000502:physiology; D011817:Rabbits; D012160:Retina / Q000378:metabolism*; D012590:Sclera / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014222:Triamcinolone Acetonide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D014222:Triamcinolone Acetonide
keywords: Choroidal circulation; Episcleral drug-film; Episcleral-controlled release of triamcinolone; Intraocular pressure; Transscleral drug delivery