Treatment of endotoxin-induced uveitis by topical application of cyclosporine a-loaded PolyGel™ in rabbit eyes

Aws Alshamsan; Mohd Abul Kalam; Mohammad Reza Vakili; Ziyad Binkhathlan; Mohammad Raish; Raisuddin Ali; Turki A Alturki; Nazila Safaei Nikouei; Afsaneh Lavasanifar

doi:10.1016/j.ijpharm.2019.118573

Treatment of endotoxin-induced uveitis by topical application of cyclosporine a-loaded PolyGel™ in rabbit eyes

Int J Pharm. 2019 Oct 5:569:118573. doi: 10.1016/j.ijpharm.2019.118573. Epub 2019 Jul 26.

Authors

Aws Alshamsan¹, Mohd Abul Kalam², Mohammad Reza Vakili³, Ziyad Binkhathlan², Mohammad Raish⁴, Raisuddin Ali², Turki A Alturki⁵, Nazila Safaei Nikouei³, Afsaneh Lavasanifar⁶

Affiliations

¹ Nanobiotechnology Unit, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address: aalshamsan@ksu.edu.sa.
² Nanobiotechnology Unit, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
³ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
⁴ Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁵ Ophthalmology Unit, King Abdullah bin Abdulaziz University Hospital, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁶ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H7, Canada; Department of Chemical and Material Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada. Electronic address: afsaneh@ualberta.ca.

PMID: 31356955
DOI: 10.1016/j.ijpharm.2019.118573

Abstract

The main objective of this study was to investigate the potential of poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone)-block-poly(ethylene glycol)-block-poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone) (PCBCL-b-PEG-b-PCBCL; denoted as PolyGel™) as an in situ gel system for ocular delivery of CyA. The newly developed formulation was systematically assessed and its profile was compared to Restasis®, 0.5% CyA extemporaneous preparation, and CyA-loaded poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) a non-gelling micelle formulation. In vivo Draize test showed that CyA-loaded PolyGel™ was well tolerated with only moderate irritation that resolved within 24 h. Both ex vivo corneal permeation and in vivo pharmacokinetics in aqueous humor (AqH) showed sustained release of CyA from PolyGel™. Non-compartmental analysis of CyA concentrations in AqH showed significant changes in pharmacokinetic parameters of CyA among different formulations. The highest C_max and AUC_0-∞ in AqH were achieved with Restasis® followed by PolyGel™. Nonetheless, CyA-loaded PolyGel™ had approximately 87% longer t_1/2 for CyA compared to Restasis®. Pharmacological and histopathological studies were performed on an endotoxin-induced uveitis rabbit model, where CyA-loaded PolyGel™ showed a comparable profile to Restasis®. Our results point to a great potential of PolyGel™ as ocular drug delivery carrier.

Keywords: Cyclosporine A; Ocular; PolyGel™; Polymeric micelles; Restasis®; Uveitis.

MeSH terms

Administration, Topical
Animals
Aqueous Humor / metabolism
Cyclosporine / administration & dosage*
Cyclosporine / pharmacokinetics
Drug Carriers / administration & dosage*
Eye / drug effects
Eye / metabolism
Immunosuppressive Agents / administration & dosage*
Immunosuppressive Agents / pharmacokinetics
Lipopolysaccharides
Male
Polyesters / administration & dosage*
Polyesters / pharmacokinetics
Rabbits
Uveitis / chemically induced
Uveitis / drug therapy*

Substances

Drug Carriers
Immunosuppressive Agents
Lipopolysaccharides
Polyesters
Cyclosporine