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Cyclosporine A eyedrops with self-nanoemulsifying drug delivery systems have improved physicochemical properties and efficacy against dry eye disease in a murine dry eye model


Autoři: Seung Pil Bang aff001;  Chang Yeor Yeon aff003;  Nirpesh Adhikari aff003;  Sanjiv Neupane aff003;  Harim Kim aff001;  Dong Cheol Lee aff001;  Myeong Jin Son aff001;  Hyun Gyo Lee aff001;  Jae-Young Kim aff003;  Jong Hwa Jun aff001
Působiště autorů: Department of Ophthalmology, Keimyung University School of Medicine, Dongsan Medical Centre, Daegu, Republic of Korea aff001;  Department of Biomedical Engineering, University of Rochester, Rochester, New York, United States of America aff002;  Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224805

Souhrn

Purpose

We aimed to compare the physicochemical properties and in vivo efficacy of commercially available nanoemulsion cyclosporine A (CsA) eyedrops in benzalkonium chloride (BAC)-induced dry eye disease (DED).

Methods

Particle size analysis was performed on conventional 0.05% CsA (Restasis, C-CsA) and two new types of 0.05% CsA eyedrops based on a self-nanoemulsifying drug delivery system (SNEDDS, SNEDDS-N and -T). Turbidometry, pH measurements and instability indices of each CsA solution were measured. DED was induced with BAC, and animals were treated with vehicle or CsA preparations. Tear volume and fluorescein staining scores were evaluated on days 7 and 14. Eyes were enucleated and subjected to IHC, TUNEL staining, periodic acid-Schiff (PAS) staining, real-time PCR and western blotting.

Results

Both SNEDDSs had lower and more uniform particle size distribution than C-CsA, and a similar optical density to phosphate-buffered saline and stable pH, in contrast to the high turbidity and unstable pH of C-CsA. Aqueous tear volume and fluorescein staining scores were improved in C-CsA- and SNEDDS-treated mice. Numbers of PAS-positive goblet cells and levels of inflammatory mediators were decreased by both C-CsA and SNEDDS, although SNEDDS resolved inflammation more effectively than C-CsA.

Conclusions

Cyclosporine A eyedrops with SNEDDS have improved physicochemical properties and treatment efficacy in BAC-induced DED.

Klíčová slova:

Apoptosis – Cornea – Cytokines – Emulsions – Eyes – Inflammation – Nanoparticles – Turbidity


Zdroje

1. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276–83. Epub 2017/07/25. doi: 10.1016/j.jtos.2017.05.008 28736335.

2. Niederkorn JY, Stern ME, Pflugfelder SC, De Paiva CS, Corrales RM, Gao J, et al. Desiccating stress induces T cell-mediated Sjogren’s Syndrome-like lacrimal keratoconjunctivitis. J Immunol. 2006;176(7):3950–7. Epub 2006/03/21. doi: 10.4049/jimmunol.176.7.3950 16547229.

3. Zhang X, Chen W, De Paiva CS, Volpe EA, Gandhi NB, Farley WJ, et al. Desiccating stress induces CD4+ T-cell-mediated Sjogren’s syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-gamma. Am J Pathol. 2011;179(4):1807–14. Epub 2011/08/17. doi: 10.1016/j.ajpath.2011.06.030 21843497.

4. Lee SY, Han SJ, Nam SM, Yoon SC, Ahn JM, Kim TI, et al. Analysis of tear cytokines and clinical correlations in Sjogren syndrome dry eye patients and non-Sjogren syndrome dry eye patients. Am J Ophthalmol. 2013;156(2):247–53.e1. Epub 2013/06/12. doi: 10.1016/j.ajo.2013.04.003 23752063.

5. Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438–510. Epub 2017/07/25. doi: 10.1016/j.jtos.2017.05.011 28736340.

6. Utine CA, Stern M, Akpek EK. Clinical review: topical ophthalmic use of cyclosporin A. Ocul Immunol Inflamm. 2010;18(5):352–61. Epub 2010/08/26. doi: 10.3109/09273948.2010.498657 20735287.

7. Power WJ, Mullaney P, Farrell M, Collum LM. Effect of topical cyclosporin A on conjunctival T cells in patients with secondary Sjogren’s syndrome. Cornea. 1993;12(6):507–11. Epub 1993/11/01. doi: 10.1097/00003226-199311000-00008 8261782.

8. 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(3):307–18. Epub 2003/11/07. doi: 10.1016/s0939-6411(03)00138-3 14602172.

9. Lallemand F, Schmitt M, Bourges JL, Gurny R, Benita S, Garrigue JS. Cyclosporine A delivery to the eye: A comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm. 2017;117:14–28. Epub 2017/03/21. doi: 10.1016/j.ejpb.2017.03.006 28315447.

10. Agarwal P, Rupenthal ID. Modern approaches to the ocular delivery of cyclosporine A. Drug Discov Today. 2016;21(6):977–88. Epub 2016/04/16. doi: 10.1016/j.drudis.2016.04.002 27080149.

11. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000;107(4):631–9. Epub 2000/04/18. doi: 10.1016/s0161-6420(99)00176-1 10768324.

12. Coursey TG, Wassel RA, Quiambao AB, Farjo RA. Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease. Transl Vis Sci Technol. 2018;7(5):24. Epub 2018/10/17. doi: 10.1167/tvst.7.5.24 30323997.

13. Kim HS, Kim TI, Kim JH, Yoon KC, Hyon JY, Shin KU, et al. Evaluation of Clinical Efficacy and Safety of a Novel Cyclosporin A Nanoemulsion in the Treatment of Dry Eye Syndrome. J Ocul Pharmacol Ther. 2017;33(7):530–8. Epub 2017/08/02. doi: 10.1089/jop.2016.0164 28759302.

14. Tadros T. Application of rheology for assessment and prediction of the long-term physical stability of emulsions. Adv Colloid Interface Sci. 2004;108–109:227–58. Epub 2004/04/10. doi: 10.1016/j.cis.2003.10.025 15072944.

15. Rehman FU, Shah KU, Shah SU, Khan IU, Khan GM, Khan A. From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS). Expert Opin Drug Deliv. 2017;14(11):1325–40. Epub 2016/08/04. doi: 10.1080/17425247.2016.1218462 27485144.

16. Shahba AA, Mohsin K, Alanazi FK. Novel self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of cinnarizine: design, optimization, and in-vitro assessment. AAPS PharmSciTech. 2012;13(3):967–77. doi: 10.1208/s12249-012-9821-4 22760454.

17. Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol. 2016;10:2433–41. doi: 10.2147/OPTH.S118409 27994437.

18. Mehta RC, Head LF, Hazrati AM, Parr M, Rapp RP, DeLuca PP. Fat emulsion particle-size distribution in total nutrient admixtures. Am J Hosp Pharm. 1992;49(11):2749–55. Epub 1992/11/01. 1471641.

19. Tadros T, Izquierdo P, Esquena J, Solans C. Formation and stability of nano-emulsions. Adv Colloid Interface Sci. 2004;108–109:303–18. Epub 2004/04/10. doi: 10.1016/j.cis.2003.10.023 15072948.

20. Einhorn-Stoll U, Weiss M, Kunzek H. Influence of the emulsion components and preparation method on the laboratory-scale preparation of o/w emulsions containing different types of dispersed phases and/or emulsifiers. Nahrung. 2002;46(4):294–301. Epub 2002/09/13. doi: 10.1002/1521-3803(20020701)46:4<294::AID-FOOD294>3.0.CO;2-2 12224428.

21. Saheki A, Seki J, Nakanishi T, Tamai I. Effect of back pressure on emulsification of lipid nanodispersions in a high-pressure homogenizer. Int J Pharm. 2012;422(1–2):489–94. Epub 2011/11/24. doi: 10.1016/j.ijpharm.2011.10.060 22108638.

22. Tang SY, Shridharan P, Sivakumar M. Impact of process parameters in the generation of novel aspirin nanoemulsions—comparative studies between ultrasound cavitation and microfluidizer. Ultrason Sonochem. 2013;20(1):485–97. Epub 2012/05/29. doi: 10.1016/j.ultsonch.2012.04.005 22633626.

23. Sadeghpour Galooyak S, Dabir B. Three-factor response surface optimization of nano-emulsion formation using a microfluidizer. J Food Sci Technol. 2015;52(5):2558–71. Epub 2015/04/22. doi: 10.1007/s13197-014-1363-1 25892755.

24. Barnadas-Rodriguez R, Sabes M. Factors involved in the production of liposomes with a high-pressure homogenizer. Int J Pharm. 2001;213(1–2):175–86. Epub 2001/02/13. doi: 10.1016/s0378-5173(00)00661-x 11165105.

25. Anton N, Vandamme TF. Nano-emulsions and micro-emulsions: clarifications of the critical differences. Pharm Res. 2011;28(5):978–85. Epub 2010/11/09. doi: 10.1007/s11095-010-0309-1 21057856.

26. Rao SN. Reversibility of dry eye deceleration after topical cyclosporine 0.05% withdrawal. J Ocul Pharmacol Ther. 2011;27(6):603–9. Epub 2011/10/18. doi: 10.1089/jop.2011.0073 21999340.

27. Mah F, Milner M, Yiu S, Donnenfeld E, Conway TM, Hollander DA. PERSIST: Physician’s Evaluation of Restasis((R)) Satisfaction in Second Trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clin Ophthalmol. 2012;6:1971–6. Epub 2012/12/12. doi: 10.2147/OPTH.S30261 23226002.

28. Lin Z, Liu X, Zhou T, Wang Y, Bai L, He H, et al. A mouse dry eye model induced by topical administration of benzalkonium chloride. Mol Vis. 2011;17:257–64. Epub 2011/02/02. 21283525.

29. Dogru M, Ishida K, Matsumoto Y, Goto E, Ishioka M, Kojima T, et al. Strip meniscometry: a new and simple method of tear meniscus evaluation. Invest Ophthalmol Vis Sci. 2006;47(5):1895–901. Epub 2006/04/28. doi: 10.1167/iovs.05-0802 16638996.

30. Wan KH, Chen LJ, Young AL. Efficacy and Safety of Topical 0.05% Cyclosporine Eye Drops in the Treatment of Dry Eye Syndrome: A Systematic Review and Meta-analysis. Ocul Surf. 2015;13(3):213–25. Epub 2015/06/06. doi: 10.1016/j.jtos.2014.12.006 26045239.

31. Zhang Z, Yang WZ, Zhu ZZ, Hu QQ, Chen YF, He H, et al. Therapeutic effects of topical doxycycline in a benzalkonium chloride-induced mouse dry eye model. Invest Ophthalmol Vis Sci. 2014;55(5):2963–74. Epub 2014/04/12. doi: 10.1167/iovs.13-13577 24722696.

32. Turner K, Pflugfelder SC, Ji Z, Feuer WJ, Stern M, Reis BL. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea. 2000;19(4):492–6. Epub 2000/08/06. doi: 10.1097/00003226-200007000-00018 10928765.

33. Shetty R, Ghosh A, Lim RR, Subramani M, Mihir K, Reshma AR, et al. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci. 2015;56(2):738–50. Epub 2015/02/05. doi: 10.1167/iovs.14-14831 25648341.

34. Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder SC. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci. 2004;45(12):4293–301. Epub 2004/11/24. doi: 10.1167/iovs.03-1145 15557435.

35. Seo MJ, Kim JM, Lee MJ, Sohn YS, Kang KK, Yoo M. The therapeutic effect of DA-6034 on ocular inflammation via suppression of MMP-9 and inflammatory cytokines and activation of the MAPK signaling pathway in an experimental dry eye model. Curr Eye Res. 2010;35(2):165–75. Epub 2010/02/09. doi: 10.3109/02713680903453494 20136427.

36. Chen M, Hu DN, Pan Z, Lu CW, Xue CY, Aass I. Curcumin protects against hyperosmoticity-induced IL-1beta elevation in human corneal epithelial cell via MAPK pathways. Exp Eye Res. 2010;90(3):437–43. Epub 2009/12/23. doi: 10.1016/j.exer.2009.12.004 20026325.

37. Warcoin E, Baudouin C, Gard C, Brignole-Baudouin F. In Vitro Inhibition of NFAT5-Mediated Induction of CCL2 in Hyperosmotic Conditions by Cyclosporine and Dexamethasone on Human HeLa-Modified Conjunctiva-Derived Cells. PLoS One. 2016;11(8):e0159983. Epub 2016/08/04. doi: 10.1371/journal.pone.0159983 27486749.

38. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26. Epub 2002/08/23. doi: 10.1016/s1097-2765(02)00599-3 12191486.

39. Chen M, Wang H, Chen W, Meng G. Regulation of adaptive immunity by the NLRP3 inflammasome. Int Immunopharmacol. 2011;11(5):549–54. Epub 2010/12/02. doi: 10.1016/j.intimp.2010.11.025 21118671.

40. Xie YF, Shu R, Jiang SY, Song ZC, Guo QM, Dong JC, et al. miRNA-146 negatively regulates the production of pro-inflammatory cytokines via NF-kappaB signalling in human gingival fibroblasts. J Inflamm (Lond). 2014;11(1):38. Epub 2015/01/20. doi: 10.1186/s12950-014-0038-z 25598707.

41. Zhang W, Shao M, He X, Wang B, Li Y, Guo X. Overexpression of microRNA-146 protects against oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis by inhibiting the NF-kappaB/TNF-alpha signaling pathway. Mol Med Rep. 2018;17(1):1913–8. Epub 2017/12/20. doi: 10.3892/mmr.2017.8073 29257202.

42. Liu X, Ye F, Xiong H, Hu DN, Limb GA, Xie T, et al. IL-1beta induces IL-6 production in retinal Muller cells predominantly through the activation of p38 MAPK/NF-kappaB signaling pathway. Exp Cell Res. 2015;331(1):223–31. Epub 2014/09/23. doi: 10.1016/j.yexcr.2014.08.040 25239226.

43. Wang Z, Yang Y, Yang H, Capo-Aponte JE, Tachado SD, Wolosin JM, et al. NF-kappaB feedback control of JNK1 activation modulates TRPV1-induced increases in IL-6 and IL-8 release by human corneal epithelial cells. Mol Vis. 2011;17:3137–46. Epub 2011/12/16. 22171160.

44. Zhu S, Xu X, Liu K, Gu Q, Wei F, Jin H. Peptide GC31 inhibits chemokines and ICAM-1 expression in corneal fibroblasts exposed to LPS or poly(I:C) by blocking the NF-kappaB and MAPK pathways. Exp Eye Res. 2017;164:109–17. Epub 2017/08/06. doi: 10.1016/j.exer.2017.07.017 28778400.

45. Liu Y, Kimura K, Yanai R, Chikama T, Nishida T. Cytokine, chemokine, and adhesion molecule expression mediated by MAPKs in human corneal fibroblasts exposed to poly(I:C). Invest Ophthalmol Vis Sci. 2008;49(8):3336–44. Epub 2008/07/29. doi: 10.1167/iovs.07-0972 18660424.

46. Orita T, Kimura K, Zhou HY, Nishida T. Poly(I:C)-induced adhesion molecule expression mediated by NF-{kappa}B and phosphoinositide 3-kinase-Akt signaling pathways in human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2010;51(11):5556–60. Epub 2010/06/25. doi: 10.1167/iovs.09-4909 20574012.

47. Murube J, Rivas L. Impression cytology on conjunctiva and cornea in dry eye patients establishes a correlation between squamous metaplasia and dry eye clinical severity. Eur J Ophthalmol. 2003;13(2):115–27. Epub 2003/04/17. doi: 10.1177/112067210301300201 12696629.

48. Li S, Nikulina K, DeVoss J, Wu AJ, Strauss EC, Anderson MS, et al. Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease. Invest Ophthalmol Vis Sci. 2008;49(1):34–41. Epub 2008/01/04. doi: 10.1167/iovs.07-0685 18172072.

49. Chen YT, Li S, Nikulina K, Porco T, Gallup M, McNamara N. Immune profile of squamous metaplasia development in autoimmune regulator-deficient dry eye. Mol Vis. 2009;15:563–76. Epub 2009/04/15. 19365590.

50. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182(3):311–22. Epub 2000/02/01. doi: 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9 10653597.

51. Wu H, Zhang H, Wang C, Wu Y, Xie J, Jin X, et al. Genoprotective effect of hyaluronic acid against benzalkonium chloride-induced DNA damage in human corneal epithelial cells. Mol Vis. 2011;17:3364–70. Epub 2012/01/06. 22219631.

52. Xiao X, He H, Lin Z, Luo P, He H, Zhou T, et al. Therapeutic effects of epidermal growth factor on benzalkonium chloride-induced dry eye in a mouse model. Invest Ophthalmol Vis Sci. 2012;53(1):191–7. Epub 2011/12/14. doi: 10.1167/iovs.11-8553 22159022.

53. Gao J, Sana R, Calder V, Calonge M, Lee W, Wheeler LA, et al. Mitochondrial permeability transition pore in inflammatory apoptosis of human conjunctival epithelial cells and T cells: effect of cyclosporin A. Invest Ophthalmol Vis Sci. 2013;54(7):4717–33. Epub 2013/06/20. doi: 10.1167/iovs.13-11681 23778874.

54. Pflugfelder SC, De Paiva CS, Villarreal AL, Stern ME. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008;27(1):64–9. Epub 2008/02/05. doi: 10.1097/ICO.0b013e318158f6dc 18245969.

55. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000;118(11):1489–96. Epub 2000/11/14. doi: 10.1001/archopht.118.11.1489 11074805.

56. Stern ME, Gao J, Schwalb TA, Ngo M, Tieu DD, Chan CC, et al. Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye. Invest Ophthalmol Vis Sci. 2002;43(8):2609–14. Epub 2002/07/31. 12147592.

57. Pflugfelder SC, De Paiva CS, Moore QL, Volpe EA, Li DQ, Gumus K, et al. Aqueous Tear Deficiency Increases Conjunctival Interferon-gamma (IFN-gamma) Expression and Goblet Cell Loss. Invest Ophthalmol Vis Sci. 2015;56(12):7545–50. Epub 2015/12/01. doi: 10.1167/iovs.15-17627 26618646.

58. Barbosa FL, Xiao Y, Bian F, Coursey TG, Ko BY, Clevers H, et al. Goblet Cells Contribute to Ocular Surface Immune Tolerance-Implications for Dry Eye Disease. Int J Mol Sci. 2017;18(5). Epub 2017/05/06. doi: 10.3390/ijms18050978 28475124.


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