Evaluation of cyclosporine A eye penetration after administration of liposomal or conventional forms in animal model

Document Type: Research Paper


1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Eye Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5 Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran



A lot of researches have investigated the effects of topical cyclosporine A on the eye surface layers’ diseases. By now the main limitation in cyclosporine application is the low permeation of the drug into the posterior segments of the eye. The aim of present study was to formulate high permeable dosage form can be beneficial in the topical treatment of the uveitis. To reach higher corneal drug absorption and drug concentration in the posterior segments of the eye, 3 nanoliposomal formulations containing 0.5 mg/ml cyclosporine A were prepared. Liposomal formulations and the commercial product (Restasis®) were instilled in the right and left eyes of the rabbits, respectively. The rabbits were killed in the 3, 7, 14 and 28 days of study and the aqueous humor and vitreous were extracted. Mean size of liposomal formulation number 1, number 2 and number 3 were 107.2 ± 0.7, 129.3±0.9 and 144.8±1.8 nm and their zeta potential were -5.0±1.7, -5.5±2.3 and 44.6±6.2 mV, respectively. Results of ocular analysis showed that the liposomal formulations could increase the concentration of the drug in the aqueous and vitreous like Restasis®. But, in contrast with what has been expected the findings of this study implicate nanoliposomal formulations prepared could not make a significant difference in concentration of the drug in aqueous and vitreous humor compared to Restasis® (anionic microemulsion). In conclusion, we can state that liposomes with the same composition as our formulations are not more efficient than microemulsion for cyclosporine as ophthalmic drug delivery.


  1. Guerra AA Jr, Cesar CC, Cherchiglia ML, Andrade EI, de Queiroz OV, Silva GD, de Assis Acurcio F. Cyclosporine versus tacrolimus in immunosuppressive maintenance regimens in renal transplants in Brazil: survival analysis from 2000 to 2004. Ann Pharmacother. 2010; 44: 192–201.
  2. Ghio L, Tarantino A, Edefonti A, Mocciaro A, Giani M, Guerra L, Berardinelli L, Vegeto A. Advantages of cyclosporine as sole immunosuppressive agent in children with transplanted kidneys. Transplantation. 1992 ; 54: 834–838.
  3. Rayhill SC, Barbeito R, Katz D, Voigt M, Labrecque D, Kirby P, Miller R, Stolpen A, Wu Y, Schmidt W. A cyclosporine-based immunosuppressive regimen may be better than tacrolimus for long-term liver allograft survival in recipients transplanted for hepatitis C. Transplant Proc. 2006; 38: 3625–3628.
  4. Malaekeh-Nikouei B, Jaafari MR, Tabassi SA, Samiei A. The enhancement of immunosuppressive effects of cyclosporine A on human T-cells using fusogenic liposomes. Colloids Surf B Biointerfaces. 2008 ; 67: 238–244.
  5. Theng JT, Ti SE, Zhou L, Chee SP, Tan D. Pharmacokinetic and toxicity study of an intraocular cyclosporine DDS in the anterior segment of rabbit eyes. Invest Ophthalmol Vis Sci. 2003; 44: 4895–4899.
  6. BenEzra D, and Maftzir G. Ocular penetration of cyclosporine A. Investigative Ophthalmology & Visual Science. 1990; 31: 1362-1366.
  7. Zaghloul AA, Hussain A, Khan MA, Ahsan F. Development of a HPLC method for the determination of cyclosporin-A in rat blood and plasma using naproxen as an internal standard. J Pharm Biomed Anal. 2003; 31:1101–1107
  8. Yee GC, Gmur DJ, Kennedy MS. Liquid-chromatographic determination of cyclosporine in serum with use of a rapid extraction procedure. Clin Chem. 1982; 28:2269–2271
  9. BenEzra D, Maftzir G, de Courten C, Timonen P. Ocular penetration of cyclosporin A. III: The human eye. Br J Ophthalmol. 1990; 74: 350–352
  10. De Campos AM, Sanchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. Int J Pharm. 2001; 224:159–168
  11. Mora P, Ceglarek U, Manzotti F, Zavota L, Carta A, Aldigeri R, Orsoni JG. Cyclosporin A in the ocular fluids of uveitis patients following long-term systemic administration. Graefes Arch Clin Exp Ophthalmol. 2008; 246: 1047–1052.
  12.  Lallemand F, Felt-Baeyens O, Besseghir K, Behar-Cohen F, Gurny R. Cyclosporine A delivery to the eye: a pharmaceutical challenge. Eur J Pharm Biopharm. 2003; 56: 307–318
  13. Donnenfeld E, and Pflugfelder S C. Topical ophthalmic cyclosporine: pharmacology and clinical uses. Survey of Ophthalmology. 2009; 54, 321–338.
  14. Mosallaei N, Banaee T, Farzadnia M, Abedini E, Ashraf H, and Malaekeh-Nikouei B. Safety Evaluation of Nanoliposomes Containing Cyclosporine A after Ocular Administration. Current Eye Research. 2012; 37: 453–456.
  15. Daonilo D L. Liposomes in gene delivery. CRC press. 1997; 1: 67-91
  16. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005; 4: 145–160.
  17. Cortesi R, Argnani R, Esposito E, Dalpiaz A, Scatturin A, Bortolotti F, Lufino M, Guerrini R, Cavicchioni G, Incorvaia C, Menegatti E, and Manservigi R. Cationic liposomes as potential carriers for ocular administration of peptides with anti-herpetic activity. International Journal of Pharmaceutics. 2006; 317: 90–100.
  18. Sahoo S K, Dilnawaz F, and Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discovery Today. 2008; 13: 144-151.
  19. Lee V, Urrea P, Smith R, and Schanzlin D. Ocular Drug Bioavailability From Topically Applied Liposomes. Surv Ophthalmol. 1985; 29:335-348.