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Pharmaceutical Research

, 36:36 | Cite as

Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease

  • Abhirup Mandal
  • Vrinda Gote
  • Dhananjay Pal
  • Abayomi Ogundele
  • Ashim K. MitraEmail author
Expert Review
Part of the following topical collections:
  1. Ophthalmic Drug Discovery and Development

Abstract

Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.

Key words

tear micelles OTX-101 formulation keratoconjunctivits sicca (KCS) non-ionic ocular drug delivery 

Abbreviations

APCs

Antigen presenting cells

AUC

Area under curve

BSS

Balanced salt solution

CaN

Calcineurin

CAPIR

Circulation, accumulation, penetration, internalization and release

CMC

Critical micelle concentration

CsA

Cyclosporine

FK

Filamentary keratitis

ICAM-1

Intercellular adhesion molecule 1

IC

Impression cytology

IL-2

Interleukin 2

IOP

Intraocular pressure

KCS

Keratoconjunctivitis sicca

LFU

Lacrimal functional unit

MGD

Meibomian gland dysfunction

MMP-9

Matrix metallopeptidase 9

MPTP

Mitochondrial permeability transition pore

NF-ATc

Cytoplasmic component of nuclear factor of activated T cells

NF-ATn

Nuclear component of nuclear factor of activated T cells

PEG

Polyethylene glycol

PK

Pharmacokinetics

VCAM-1

Vascular cell adhesion molecule-1

Notes

Acknowledgements and Disclosures

The authors would like to acknowledge the contributions of Dr. Kishore Cholkar and Dr. Brian C. Gilger for the pharmacokinetic portions of the pre-clinical studies. The authors also acknowledge Joseph Tauber (Tauber Eye Centre), Sidney L. Weiss (Auven Therapeutics), William Kramer (Kramer consulting LLC) and Poonam Velagaleti (I-novion, Inc.) for their contributions in the various phases of the clinical studies. Authors also acknowledge Ocular Technologies Sarl (now wholly owned subsidiary of Sun Pharmaceutical Industries) and Sun Pharmaceutical Industries for sponsoring, conducting, monitoring and analyzing the clinical studies.

Supplementary material

11095_2018_2556_MOESM1_ESM.docx (22 kb)
ESM 1 (DOCX 21 kb)

References

  1. 1.
    Javadi MA, Feizi S. Dry eye syndrome. J Ophthalmic Vis Res. 2011;6(3):192–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol. 2009;3:405–12.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Hawkes N. US's $2bn annual spend on dry eye disease "brings tears to your eyes," say critics. BMJ. 2018;360:k492.PubMedGoogle Scholar
  4. 4.
    Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea. 2011;30(4):379–87.PubMedGoogle Scholar
  5. 5.
    Tsubota K. Tear dynamics and dry eye. Prog Retin Eye Res. 1998;17(4):565–96.PubMedGoogle Scholar
  6. 6.
    Butovich IA. Tear film lipids. Exp Eye Res. 2013;117:4–27.PubMedGoogle Scholar
  7. 7.
    Cwiklik L. Tear film lipid layer: a molecular level view. Biochim Biophys Acta. 2016;1858(10):2421–30.PubMedGoogle Scholar
  8. 8.
    Zhang X, VJ M, Qu Y, He X, Ou S, Bu J, et al. Dry Eye Management: Targeting the Ocular Surface Microenvironment. Int J Mol Sci. 2017;18(7).Google Scholar
  9. 9.
    Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17(6):584–9.PubMedGoogle Scholar
  10. 10.
    Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface. 2007;5(2):179–193.Google Scholar
  11. 11.
    Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015;112(5):71–81 quiz 82.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Reyes JL, Vannan DT, Eksteen B, Avelar IJ, Rodriguez T, Gonzalez MI, et al. Innate and adaptive cell populations driving inflammation in dry eye disease. Mediat Inflamm. 2018;2018:2532314.Google Scholar
  13. 13.
    Kuklinski E, Asbell PA. Sjogren's syndrome from the perspective of ophthalmology. Clin Immunol. 2017;182:55–61.PubMedGoogle Scholar
  14. 14.
    Perry HD. Dry eye disease: pathophysiology, classification, and diagnosis. Am J Manag Care. 2008;14(3 Suppl):S79–87.PubMedGoogle Scholar
  15. 15.
    Sullivan DA, Dana R, Sullivan RM, Krenzer KL, Sahin A, Arica B, et al. Meibomian gland dysfunction in primary and secondary Sjogren syndrome. Ophthalmic Res. 2018;59(4):193–205.PubMedGoogle Scholar
  16. 16.
    Milner MS, Beckman KA, Luchs JI, Allen QB, Awdeh RM, Berdahl J, et al. Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;27(Suppl 1):3–47.PubMedGoogle Scholar
  17. 17.
    Roy NS, Wei Y, Kuklinski E, Asbell PA. The growing need for validated biomarkers and endpoints for dry eye clinical research. Invest Ophthalmol Vis Sci. 2017;58(6):BIO1–BIO19.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Messmer EM, von Lindenfels V, Garbe A, Kampik A. Matrix metalloproteinase 9 testing in dry eye disease using a commercially available point-of-care immunoassay. Ophthalmology. 2016;123(11):2300–8.PubMedGoogle Scholar
  19. 19.
    Buckley RJ. Assessment and management of dry eye disease. Eye. 2018;32(2):200–3.PubMedGoogle Scholar
  20. 20.
    Friedman NJ. Impact of dry eye disease and treatment on quality of life. Curr Opin Ophthalmol. 2010;21(4):310–6.PubMedGoogle Scholar
  21. 21.
    Levy O, Labbe A, Borderie V, Laroche L, Bouheraoua N. Topical cyclosporine in ophthalmology: pharmacology and clinical indications. J Fr Ophtalmol. 2016;39(3):292–307.PubMedGoogle Scholar
  22. 22.
    Schultz C. Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis. 2014;6:37–42.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Leonardi A, Flamion B, Baudouin C. Keratitis in dry eye disease and topical Ciclosporin a. Ocul Immunol Inflamm. 2017;25(4):577–86.PubMedGoogle Scholar
  24. 24.
    Utine CA, Stern M, Akpek EK. Clinical review: topical ophthalmic use of cyclosporin a. Ocul Immunol Inflamm. 2010;18(5):352–61.PubMedGoogle Scholar
  25. 25.
    Boboridis KG, Konstas AGP. Evaluating the novel application of cyclosporine 0.1% in ocular surface disease. Expert Opin Pharmacother. 2018;19(9):1027–39.PubMedGoogle Scholar
  26. 26.
    Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–25.PubMedGoogle Scholar
  27. 27.
    Pietro DCaAD. Systemic Cyclosporin in the treatment of psoriasis. IntechOpen 2012.Google Scholar
  28. 28.
    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.PubMedGoogle Scholar
  29. 29.
    Sy A, O'Brien KS, Liu MP, Cuddapah PA, Acharya NR, Lietman TM, et al. Expert opinion in the management of aqueous deficient dry eye disease (DED). BMC Ophthalmol. 2015;15:133.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Bell TA, Hunnisett AG. Cyclosporin a: tissue levels following topical and systemic administration to rabbits. Br J Ophthalmol. 1986;70(11):852–5.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Pfau B, Kruse FE, Rohrschneider K, Zorn M, Fiehn W, Burk RO, et al. Comparison between local and systemic administration of cyclosporin a on the effective level in conjunctiva, aqueous humor and serum. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 1995;92(6):833–9.Google Scholar
  32. 32.
    Ganesan V, Milford DV, Taylor CM, Hulton SA, Parvaresh S, Ramani P. Cyclosporin-related nephrotoxicity in children with nephrotic syndrome. Pediatr Nephrol. 2002;17(3):225–6 author reply 227.PubMedGoogle Scholar
  33. 33.
    el-Asrar AM, Tabbara KF, Geboes K, Missotten L, Desmet V. An immunohistochemical study of topical cyclosporine in vernal keratoconjunctivitis. Am J Ophthalmol. 1996;121(2):156–61.PubMedGoogle Scholar
  34. 34.
    Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590–8.PubMedGoogle Scholar
  35. 35.
    Parrilha LR, Nai GA, Giuffrida R, Barbero RC, Padovani LD, Pereira RH, et al. Comparison of 1% cyclosporine eye drops in olive oil and in linseed oil to treat experimentally-induced keratoconjunctivitis sicca in rabbits. Arq Bras Oftalmol. 2015;78(5):295–9.PubMedGoogle Scholar
  36. 36.
    Benitez del Castillo JM, del Aguila C, Duran S, Hernandez J, Garcia Sanchez J. Influence of topically applied cyclosporine a in olive oil on corneal epithelium permeability. Cornea. 1994;13(2):136–40.PubMedGoogle Scholar
  37. 37.
    Williams DL. A comparative approach to topical cyclosporine therapy. Eye. 1997;11(Pt 4):453–64.PubMedGoogle Scholar
  38. 38.
    Agarwal P, Rupenthal ID. Modern approaches to the ocular delivery of cyclosporine a. Drug Discov Today. 2016;21(6):977–88.PubMedGoogle Scholar
  39. 39.
    Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin a ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin a phase 2 study group. Ophthalmology. 2000;107(5):967–74.PubMedGoogle Scholar
  40. 40.
    Prabhu SS, Shtein RM, Michelotti MM, Cooney TM. Topical cyclosporine a 0.05% for recurrent anterior uveitis. Br J Ophthalmol. 2016;100(3):345–7.PubMedGoogle Scholar
  41. 41.
    Rhee MK, Mah FS. Clinical utility of cyclosporine (CsA) ophthalmic emulsion 0.05% for symptomatic relief in people with chronic dry eye: a review of the literature. Clin Ophthalmol. 2017;11:1157–66.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Hoy SM. Ciclosporin ophthalmic emulsion 0.1%: a review in severe dry eye disease. Drugs. 2017;77(17):1909–16.PubMedGoogle Scholar
  43. 43.
    Boujnah Y, Mouchel R, El-Chehab H, Dot C, Burillon C, Kocaba V. Prospective, monocentric, uncontrolled study of efficacy, tolerance and adherence of cyclosporin 0.1% for severe dry eye syndrome. J Fr Ophtalmol. 2018;41(2):129–35.PubMedGoogle Scholar
  44. 44.
    Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clinical investigation. 2015;5(3):267–85.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Baudouin C, de la Maza MS, Amrane M, Garrigue JS, Ismail D, Figueiredo FC, Leonardi A. One-year efficacy and safety of 0.1% cyclosporine a cationic emulsion in the treatment of severe dry eye disease. Eur J Ophthalmol 2017:0.Google Scholar
  46. 46.
    Stonecipher KG, Chia J, Onyenwenyi A, Villanueva L, Hollander DA. Health claims database study of cyclosporine ophthalmic emulsion treatment patterns in dry eye patients. Ther Clin Risk Manag. 2013;9:409–15.PubMedPubMedCentralGoogle Scholar
  47. 47.
    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. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2017;117:14–28.Google Scholar
  48. 48.
    Vaishya RD, Khurana V, Patel S, Mitra AK. Controlled ocular drug delivery with nanomicelles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6(5):422–37.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kamaleddin MA. Nano-ophthalmology: applications and considerations. Nanomedicine. 2017;13(4):1459–72.PubMedGoogle Scholar
  50. 50.
    Irfan M, Usman M, Mansha A, Rasool N, Ibrahim M, Rana UA, et al. Thermodynamic and spectroscopic investigation of interactions between reactive red 223 and reactive orange 122 anionic dyes and cetyltrimethyl ammonium bromide (CTAB) cationic surfactant in aqueous solution. TheScientificWorldJOURNAL. 2014;2014:540975.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Tanford C. Thermodynamics of micelle formation: prediction of micelle size and size distribution. Proc Natl Acad Sci U S A. 1974;71(5):1811–5.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Mandal A, Cholkar K, Khurana V, Shah A, Agrahari V, Bisht R, et al. Topical formulation of self-assembled antiviral prodrug Nanomicelles for targeted retinal delivery. Mol Pharm. 2017;14(6):2056–69.PubMedGoogle Scholar
  53. 53.
    Lu Y, Yue Z, Xie J, Wang W, Zhu H, Zhang E, et al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat Biomed Eng. 2018;2(5):318–25.Google Scholar
  54. 54.
    Morishima K, Sugawara S, Yoshimura T, Shibayama M. Structure and rheology of wormlike micelles formed by fluorocarbon-hydrocarbon-type hybrid Gemini surfactant in aqueous solution. Langmuir. 2017;33(24):6084–91.PubMedGoogle Scholar
  55. 55.
    Dhakal S, Sureshkumar R. Anomalous diffusion and stress relaxation in surfactant micelles. Phys Rev E. 2017;96(1–1):012605.PubMedGoogle Scholar
  56. 56.
    Paradies HH. Shape and size of a nonionic surfactant micelle. Triton X-100 in aqueous solution. J Phys Chem. 1980;84(6):599–607.Google Scholar
  57. 57.
    Dill KA, Flory PJ. Molecular organization in micelles and vesicles. Proc Natl Acad Sci. 1981;78(2):676–80.PubMedGoogle Scholar
  58. 58.
    Ahn YN, Mohan G, Kopelevich DI. Collective degrees of freedom involved in absorption and desorption of surfactant molecules in spherical non-ionic micelles. J Chem Phys. 2012;137(16):164902.PubMedGoogle Scholar
  59. 59.
    Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation Design for Anterior and Posterior Ocular Delivery. Transl Vis Sci Technol. 2015;4(3):1.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Lasic DD. Mixed micelles in drug delivery. Nature. 1992;355:279–80.PubMedGoogle Scholar
  61. 61.
    Alexander-Bryant AA, Vanden Berg-Foels WS, Wen X. Bioengineering strategies for designing targeted cancer therapies. Adv Cancer Res. 2013;118:1–59.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kim SA, Jeong KJ, Yethiraj A, Mahanthappa MK. Low-symmetry sphere packings of simple surfactant micelles induced by ionic sphericity. Proc Natl Acad Sci U S A. 2017;114(16):4072–7.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Xotta G, Mazzucco G, Salomoni VA, Majorana CE, Willam KJ. Composite behavior of concrete materials under high temperatures. Int J Solids Struct. 2015;64–65:86–99.Google Scholar
  64. 64.
    Lipfert J, Columbus L, Chu VB, Lesley SA, Doniach S. Size and shape of detergent micelles determined by small-angle X-ray scattering. J Phys Chem B. 2007;111(43):12427–38.PubMedGoogle Scholar
  65. 65.
    Chen H, Kim S, Li L, Wang S, Park K, Cheng JX. Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Forster resonance energy transfer imaging. Proc Natl Acad Sci U S A. 2008;105(18):6596–601.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Wang J, Mao W, Lock LL, Tang J, Sui M, Sun W, et al. The role of micelle size in tumor accumulation, penetration, and treatment. ACS Nano. 2015;9(7):7195–206.PubMedGoogle Scholar
  67. 67.
    Chopra P, Hao J, Li SK. Iontophoretic transport of charged macromolecules across human sclera. Int J Pharm. 2010;388(1–2):107–13.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Komai Y, Ushiki T. The three-dimensional organization of collagen fibrils in the human cornea and sclera. Invest Ophthalmol Vis Sci. 1991;32(8):2244–58.PubMedGoogle Scholar
  69. 69.
    Motolko M, Breslin CW. The effect of pH and osmolarity on the ability of tolerate artificial tears. Am J Ophthalmol. 1981;91(6):781–4.PubMedGoogle Scholar
  70. 70.
    Suknuntha K, Tantishaiyakul V, Worakul N, Taweepreda W. Characterization of muco- and bioadhesive properties of chitosan, PVP, and chitosan/PVP blends and release of amoxicillin from alginate beads coated with chitosan/PVP. Drug Dev Ind Pharm. 2011;37(4):408–18.PubMedGoogle Scholar
  71. 71.
    Cholkar K, Gilger BC, Mitra AK. Topical delivery of aqueous micellar resolvin E1 analog (RX-10045). Int J Pharm. 2016;498(1–2):326–34.PubMedGoogle Scholar
  72. 72.
    Ashim K. Mitra SLW, Eugene J. McNally topical formulations and uses thereof. In. USA: Sun Pharma Global FZE; 2015.Google Scholar
  73. 73.
    Mandal A, Pal D, Agrahari V, Trinh HM, Joseph M, Mitra AK. Ocular delivery of proteins and peptides: challenges and novel formulation approaches. Adv Drug Deliv Rev. 2018;126:67–95.PubMedGoogle Scholar
  74. 74.
    Mandal A, Bisht R, Rupenthal ID, Mitra AK. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Control Release. 2017;248:96–116.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Hughes PM, Olejnik O, Chang-Lin JE, Wilson CG. Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev. 2005;57(14):2010–32.PubMedGoogle Scholar
  76. 76.
    Hernandez C, Garcia-Ramirez M, Corraliza L, Fernandez-Carneado J, Farrera-Sinfreu J, Ponsati B, et al. Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes. Diabetes. 2013;62(7):2569–78.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Schoenwald RD, Deshpande GS, Rethwisch DG, Barfknecht CF. Penetration into the anterior chamber via the conjunctival/scleral pathway. J Ocul Pharmacol Ther. 1997;13(1):41–59.PubMedGoogle Scholar
  78. 78.
    Maurice DM. Drug delivery to the posterior segment from drops. Surv Ophthalmol. 2002;47(Suppl 1):S41–52.PubMedGoogle Scholar
  79. 79.
    Cholkar K. Topical clear aqueous Nanomicellar formulations for anterior and posterior ocular drug delivery. In. Kansas City University of Missouri – Kansas City; 2015.Google Scholar
  80. 80.
    Luschmann C, Herrmann W, Strauss O, Luschmann K, Goepferich A. Ocular delivery systems for poorly soluble drugs: an in-vivo evaluation. Int J Pharm. 2013;455(1–2):331–7.PubMedGoogle Scholar
  81. 81.
    Ashim K. Mitra PRV, Ulrich M. Grau Topical Drug Delivery Systems For Ophthalmic Use. In.: Aurinia Pharmaceuticals Inc Apr. 28, 2015.Google Scholar
  82. 82.
    Acheampong AA, Shackleton M, Tang-Liu DD, Ding S, Stern ME, Decker R. Distribution of cyclosporin a in ocular tissues after topical administration to albino rabbits and beagle dogs. Curr Eye Res. 1999;18(2):91–103.PubMedGoogle Scholar
  83. 83.
    Schwartz LM, Woloshin S. A clear-eyed view of Restasis and chronic dry eye disease. JAMA Intern Med. 2018;178(2):181–2.PubMedGoogle Scholar
  84. 84.
    Gilger SLWWKPVBC. Ocular distribution of cyclosporine following topical administration of OTX-101 in New Zealand white rabbits. In.The Association for Research in Vision and Ophthalmology. Honolulu, Hawaii; 2018.Google Scholar
  85. 85.
    Tauber J, Schechter BA, Bacharach J, Toyos MM, Smyth-Medina R, Weiss SL, et al. A phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 2018;12:1921–9.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Sun Pharma Announces U.S. FDA Approval of CEQUA™ to Treat Dry Eye Disease. Sun Pharmaceutical Industries Ltd.; Available from: https://www.businesswire.com/news/home/20180815005765/en/Sun-Pharma-Announces-U.S.-FDA-Approval-CEQUA%E2%84%A2. Accessed 29 Nov 2018.
  87. 87.
    Sheppard JD, Torkildsen GL, Lonsdale JD, D'Ambrosio FA Jr, McLaurin EB, Eiferman RA, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014;121(2):475–83.PubMedGoogle Scholar
  88. 88.
    Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, et al. Investigators O-. Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology. 2015;122(12):2423–31.PubMedGoogle Scholar
  89. 89.
    Jodi Luchs M. Phase 3 Clinical Results of Cyclosporine 0.09% in a New Nanomicellar Ophthalmic Solution to Treatment Keratoconjunctivitis Sicca. In.American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting Washington, DC; 2018.Google Scholar
  90. 90.
    Lifitegrast (Xiidra) for Dry Eye Disease. Jama. 2017;317(14):1473–1474.Google Scholar
  91. 91.
    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.PubMedGoogle Scholar
  92. 92.
    Schultz C. Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis. 2013;5:5–10.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Abidi A, Shukla P, Ahmad A. Lifitegrast: a novel drug for treatment of dry eye disease. J Pharmacol Pharmacother. 2016;7(4):194–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Pharmacology and Pharmaceutical Sciences, School of PharmacyUniversity of MissouriKansas CityUSA
  2. 2.Sun Pharmaceutical Industries Ltd.Sun Ophthalmics Inc.PrincetonUSA
  3. 3.Department of Ophthalmology, School of MedicineUniversity of MissouriKansas CityUSA

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