• NITHISH SHEKAR Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
  • D. V. GOWDA Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
  • HITESH KUMAR Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
  • GAURAV K. JAIN Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
  • VIKAS JAIN Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India


At the air-water interface, the tear film lipid layer (TFLL), a combination of lipids and proteins plays an important role in surface tension of the tear and is necessary for the physiological hydration of the ocular surface and maintenance of ocular homeostasis. Alteration in lacrimal fluid rheology, differences in lipid constitution or down regulation of particular tear proteins are found in maximum types of ocular surface disease including dry eye disease (DED). Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation, which causes damage to the interpalpebral ocular surface and is associated with symptoms of discomfort. It results in changes on the ocular surface epithelia causing reduced tear quantity and surface sensitivity which leads to inflammation reactions. Managing this inflammation is very helpful in dry eye disease patients. In this article we revise the current understanding of tear film properties, ocular surface and review the effectiveness of topically applied tear supplements, thermo sensitive atelocollagen punctal plug, subtrasal ultrasonic transducers, novel liposome based gelling tear formation and insulin based ophthalmic delivery systems which help in restoring the healthy tear film.

Keywords: Evaporative dry eye (EDE), Keeptar, Aqueous tear deficient dry eye (ADDE), Tear break up time (TBUT)


1. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-de?cient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea 2012;31:472–8.
2. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older population. Optometry Vision Science 2008;85:668-74.
3. Barker KE, Savage NW. Burning mouth syndrome: an update on recent findings. Australian Dental J 2005;50:220-3.
4. Leiblum SR, Hayes RD, Wanser RA, Nelson JS. Vaginal dryness: a comparison of prevalence and interventions in 11 countries. J Sexual Med 2009;6:2425-33.
5. Acosta MC, Peral A, Luna C, Pintor J, Belmonte C, Gallar J. Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerve fibers. Investigative Ophthalmol Visual Sci 2004;45:2333-6.
6. 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;107:967–74.
7. Kroemer G, Martinez C. Cytokines and autoimmune disease. Clin Immunol Immunopathol 1991;61:275–95.
8. Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 y. Ophthalmology 2005;112:1790-4.
9. 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;107:631–9.
10. Kujawa A, Rozycki R. A 0, 05% cyclosporine treatment of the advanced dry eye syndrome. Klinika Oczna 2005;107:280-6.
11. Kumari A, Sharma PK, Garg VK, Garg G. Ocular inserts-advancement in therapy of eye diseases. J Adv Pharm Technol Res 2010;1:291.
12. Robinson JC. Ocular anatomy and physiology relevant to ocular drug delivery. Drugs Pharm Sci 1993;58:29-57.
13. Mitra AK. Ophthalmic drug delivery systems; 2003.
14. Chien YW. Nasal drug delivery and delivery systems. Novel Drug Delivery Systems (2nd ed.), Marcel Dekker, Inc., New York; 1992. p. 229-68.
15. Nguyen T, Latkany R. Review of hydroxypropyl cellulose ophthalmic inserts for treatment of dry eye. Clin Ophthalmol 2011;5:587.
16. Willcox MD, Argueso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, et al. TFOS DEWS II tear film report. Ocular Surface 2017;15:366-403.
17. Cher I. A new look at lubrication of the ocular surface: fluid mechanics behind the blinking eyelids. Ocular Surface 2008;6:79-86.
18. Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefe's Arch Clin Exp Ophthalmol 2006;244:109-12.
19. Nakamura M, Hikida M, Nakano T, Ito S, Hamano T, Kinoshita S. Characterization of water retentive properties of hyaluronan. Cornea 1993;12:433-6.
20. Oh HJ, Li Z, Park SH, Yoon KC. Effect of hypotonic 0.18% sodium hyaluronate eyedrops on inflammation of the ocular surface in experimental dry eye. J Ocular Pharmacol Ther 2014;30:533-42.
21. Aragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol 2002;86:181-4.
22. Lee HS, Ji YS, Yoon KC. Efficacy of hypotonic 0.18% sodium hyaluronate eye drops in patients with dry eye disease. Cornea 2014;33:946-51.
23. Li Y, Cui L, Lee HS, Kang YS, Choi W, Yoon KC. Comparison of 0.3% hypotonic and isotonic sodium hyaluronate eye drops in the treatment of experimental dry eye. Curr Eye Res 2017;42:1108-14.
24. Zheng X, Goto T, Shiraishi A, Ohashi Y. In vitro efficacy of ocular surface lubricants against dehydration. Cornea 2013;32:1260-4.
25. Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. Ocular Surface 2017;15:539-74.
26. Prabhasawat P, Tesavibul N, Kasetsuwan N. Performance profile of sodium hyaluronate in patients with lipid tear deficiency: randomised, double-blind, controlled, exploratory study. Br J Ophthalmol 2007;91:47-50.
27. Zhang X, Chen W, De Paiva CS, Corrales RM, Volpe EA, McClellan AJ, et al. Interferon-? exacerbates dry eye–induced apoptosis in conjunctiva through dual apoptotic pathways. Invest Ophthalmol Visual Sci 2011;52:6279-85.
28. Oh HJ, Li Z, Park SH, Yoon KC. Effect of hypotonic 0.18% sodium hyaluronate eyedrops on inflammation of the ocular surface in experimental dry eye. J Ocular Pharmacol Ther 2014;30:533-42.
29. Sakamoto A, Kitagawa K, Tatami A. Efficacy and retention rate of two types of silicone punctal plugs in patients with and without Sjogren syndrome. Cornea 2004;23:249-54.
30. Giovagnoli D, Graham SJ. Inferior punctal occlusion with removable silicone punctal plugs in the treatment of dry-eye related contact lens discomfort. J Am Optometric Assoc 1992;63:481-5.
31. Kaido M, Goto E, Dogru M, Tsubota K. Punctal occlusion in the management of chronic stevens–johnson syndrome. Ophthalmology 2004;111:895-900.
32. Hsu HC. Ampullary pyogenic granuloma as a complication of lacrimal plug migration. Migration 2002;2:6.
33. Nava Castaneda A, Tovilla Canales JL, Rodriguez L, Tovilla YPJL, Jones CE. Effects of lacrimal occlusion with collagen and silicone plugs on patients with conjunctivitis associated with dry eye. Cornea 2003;22:10–4.
34. Yung YH, Toda I, Sakai C, Yoshida A, Tsubota K. Punctal plugs for treatment of post-LASIK dry eye. Japanese J Ophthalmol 2012;56:208-13.
35. Kaido M, Ishida R, Dogru M, Tsubota K. Visual function changes after punctal occlusion with the treatment of short BUT type of dry eye. Cornea 2012;31:1009-13.
36. Sabti S, Halter JP, Fränkl BB, Goldblum D. Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GvHD. Bone Marrow Transplantation 2012;47:981.
37. Ibrahim OM, Dogru M, Ward SK, Matsumoto Y, Wakamatsu TH, Ishida K, et al. The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus. Invest Ophthalmol Visual Sci 2011;52:2194-8.
38. Dutton JJ, Frueh BR. Eyelid anatomy and physiology with reference to blepharoptosis. In: Evaluation and management of blepharoptosis. Springer, New York, NY; 2011. p. 13-26.
39. Cher I. Fluids of the ocular surface: concepts, functions and physics. Clin Exp Ophthalmol 2012;40:634-43.
40. Blackie CA, McMonnies CW, Korb DR. Warm compresses and the risks of elevated corneal temperature with massage. Cornea 2013;32:e146-9.
41. Nichols KK, Foulks GN, Bron AJ, Glasgow BJ, Dogru M, Tsubota K, et al. The international workshop on meibomian gland dysfunction: executive summary. Invest Ophthalmol Visual Sci 2011;52:1922-9.
42. Waterman FM, Nerlinger RE, Leeper JB. Catheter induced temperature artifacts in ultrasound hyperthermia. Int J Hyperthermia 1990;6:371-81.
43. Wang H, Ritter T, Cao W, Shung KK. High frequency properties of passive materials for ultrasonic transducers. IEEE Transactions Ultrasonics Engineering 2001;48:78-84.
44. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction. Eye Contact Lens 2003;29:96-9.
45. Corrales RM, Luo L, Chang EY, Pflugfelder SC. Effects of osmoprotectants on hyperosmolar stress in cultured human corneal epithelial cells. Cornea 2008;27:574-9.
46. X Hua, Z Su, R Deng, J Lin, DQ Li, SC Pflugfelder. Effects of l-carnitine, er-ythritol and betaine on pro-inflammatory markers in primary human corneal epi-thelial cells exposed to hyperosmotic stress. Curr Eye Res 2015;40:657–67.
47. She Y, Li J, Xiao B, Lu H, Liu H, Simmons PA, et al. Evaluation of a novel artificial tear in the prevention and treatment of dry eye in an animal model. J Ocular Pharmacol Ther 2015;31:525-30.
48. Scheiman MM, Hertle RW, Beck RW, Edwards AR, Birch E, Cotter SA, et al. Randomized trial of treatment of amblyopia in children aged 7 to 17 y. Arch Ophthalmol 2005;123:437-47.
49. Woo DM, Healey PR, Graham SL, Goldberg I. Intraocular pressure?lowering medications and long?term outcomes of selective laser trabeculoplasty. Clin Exp Ophthalmol 2015;43:320-7.
50. Giede C, Metzenauer P, Petzold U, Ellers Lenz B. Comparison of azelastine eye drops with levocabastine eye drops in the treatment of seasonal allergic conjunctivitis. Curr Med Res Opin 2000;16:153-63.
51. Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. Ocular Surface 2017;15:539-74.
52. Lanzini M, Curcio C, Colabelli Gisoldi RA, Mastropasqua A, Calienno R, Agnifili L, et al. In vivo and impression cytology study on the effect of compatible solutes eye drops on the ocular surface epithelial cell quality in dry eye patients. Mediators Inflammation 2015.
53. Occhipinti JR, Mosier MA, Lamotte J, Monji GT. Fluorophotometric measurement of human tear turnover rate. Curr Eye Res 1988;7:995-1000.
54. Maissa C, Guillon M, Simmons P, Vehige J. Effect of castor oil emulsion eyedrops on tear film composition and stability. Contact Lens Anterior Eye 2010;33:76-82.
55. She Y, Li J, Xiao B, Lu H, Liu H, Simmons PA, et al. Evaluation of a novel artificial tear in the prevention and treatment of dry eye in an animal model. J Ocular Pharmacol Ther 2015;31:525-30.
56. Tomlinson A, Madden LC, Simmons PA. Effectiveness of dry eye therapy under conditions of environmental stress. Curr Eye Res 2013;38:229-36.
57. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001;18:205-15.
58. Paimela T, Ryhanen T, Kauppinen A, Marttila L, Salminen A, Kaarniranta K. The preservative polyquaternium-1 increases cytoxicity and NF-kappa B linked inflammation in human corneal epithelial cells. Mol Vision 2012;18:1189.
59. K Kinnunen, A Kauppinen, N Piippo, A Koistinen, E Toropainen, K Kaarniranta. Cationorm shows good tolerability on human HCE-2 corneal epithelial cell cultures. Exp Eye Res 2014;120:82–9.
60. Dutescu RM, Panfil C, Schrage N. Comparison of the effects of various lubricant eye drops on the in vitro rabbit corneal healing and toxicity. Exp Toxicol Pathol 2017;69:123-9.
61. Milas M, Shi X, Rinaudo M. On the physicochemical properties of gellan gum. Biopolymers: Original Res Biomolecules 1990;30:451-64.
62. Matsukawa S, Watanabe T. Gelation mechanism and network structure of mixed solution of low-and high-acyl gellan studied by dynamic viscoelasticity, CD and NMR measurements. Food Hydrocolloids 2007;21:1355-61.
63. Chandrasekaran R, Thailambal VG. The influence of calcium ions, acetate and L-glycerate groups on the gellan double-helix. Carbohydrate Polymers 1990;12:431-42.
64. Miyoshi E, Takaya T, Nishinari K. Rheological and thermal studies of gel-sol transition in gellan gum aqueous solutions. Carbohydrate Polymers 1996;30:109-19.
65. Kumar K, Dhawan N, Sharma H, Vaidya S, Vaidya B. Bioadhesive polymers: novel tool for drug delivery. Artif Cells Nanomed Biotechnol 2014;42:274-83.
66. Tiffany JM. The viscosity of human tears. Int Ophthalmol 1991;15:371-6.
67. Gouveia SM, Tiffany JM. Human tear viscosity: an interactive role for proteins and lipids. Biochim Biophys Acta 2005;1753:155-63.
68. Abelson MB, Udell IJ, Weston JH. Normal human tear pH by direct measurement. Arch Ophthalmol 1981;99:301.
69. Yamada M, Mochizuki H, Kawai M, Yoshino M, Mashima Y. Fluorophotometric measurement of pH of human tears in vivo. Curr Eye Res 1997;16:482-6.
70. Miller D. Measurement of the surface tension of tears. Arch Ophthalmol 1969;82:368-71.
71. Nagyova B, Tiffany JM. Components responsible for the surface tension of human tears. Curr Eye Res 1999;19:4-11.
72. Han K, Woghiren OE, Priefer R. Surface tension examination of various liquid oral, nasal, and ophthalmic dosage forms. Chem Central J 2016;10:31.
73. Alves MD, Carvalheira JB, Modulo CM, Rocha EM. Tear film and ocular surface changes in diabetes mellitus. Arquivos Brasileiros De Oftalmologia 2008;71:96-103.
74. Vieira Potter VJ, Karamichos D, Lee DJ. Ocular complications of diabetes and therapeutic approaches. BioMed Res Int 2016.
75. Zhang X, Zhao L, Deng S, Sun X, Wang N. Dry eye syndrome in patients with diabetes mellitus: prevalence, etiology, and clinical characteristics. J Ophthalmol 2016.
76. Azar DT, Gipson IK. Repair of the corneal epithelial adhesion structures following keratectomy wounds in diabetic rabbits. Acta Ophthalmol 1989;67(S192):72-9.
77. DT Azar, SJ Spurr Michaud, AS Tisdale, IK Gipson. Altered epithelialbasement membrane interactions in diabetic corneas. Arch Ophthalmol 1992;110:537-40.
78. EM Rocha, AE Hirata, EM Carneiro, MJ Saad, LAJE Velloso. Impact of gender on insulin signaling pathway in lacrimal and salivary glands of rats. Endocrine 2002;18:191-9.
79. DA Cunha, EM Carneiro, M de C Alves, AG Jorge, SM de Sousa, AC Boschero, et al. Rocha, metabolism, insulin secretion by rat lacrimal glands: effects of systemic and local variables. Am J Physiol Endocrinol Metab 2005;289:E768-75.
80. Zagon IS, Sassani JW, McLaughlin PJ. Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats. Diabetes 2006;55:1141-7.
81. Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharm Res 2009;26:1197.
82. Gratieri T, Gelfuso GM, Rocha EM, Sarmento VH, de Freitas O, Lopez RF. A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery. Eur J Pharm Biopharm 2010;75:186-93.
83. Elsayed A, Al-Remawi M, Farouk A, Badwan A. Insulin-chitosan polyelectrolyte-anocomplexes: preparation, characterization and stabilization of insulin. Sudan J Med Sci 2010;5:99-109.
84. Varshousaz J, Alinagari R. Effect of citric acid as cross-linking agent on insulin loaded chitosan microspheres. Iranian Polymer J (English) 2005;14:647-56.
85. Choy YB, Park JH, Prausnitz MR. Mucoadhesive microparticles engineered for ophthalmic drug delivery. J Phys Chem Solids 2008;69:1533-6.
86. Nakamura M, Imanaka T, Sakamoto A. Diquafosol ophthalmic solution for dry eye treatment. Adv Ther 2012;29:579-89.
87. Koh S. Clinical utility of 3% diquafosol ophthalmic solution in the treatment of dry eyes. Clin Ophthalmol (Auckland, NZ) 2015;9:865.
88. Shimazaki Den S, Iseda H, Dogru M, Shimazaki J. Effects of diquafosol sodium eye drops on tear film stability in short BUT type of dry eye. Cornea 2013;32:1120-5.
89. Yamaguchi M, Nishijima T, Shimazaki J, Takamura E, Yokoi N, Watanabe H, et al. Clinical usefulness of diquafosol for real-world dry eye patients: a prospective, open-label, non-interventional, observational study. Adv Ther 2014;31:1169-81.
90. Uchino M, Yokoi N, Uchino Y, Dogru M, Kawashima M, Komuro A, et al. Prevalence of dry eye disease and its risk factors in visual display terminal users: the Osaka study. Am J Ophthalmol 2013;156:759-66.
91. Yokoi N, Uchino M, Uchino Y, Dogru M, Kawashima M, Komuro A, et al. Importance of tear film instability in dry eye disease in office workers using visual display terminals: the Osaka study. Am J Ophthalmol 2015;159:748-54.
92. Kojima T, Ibrahim OM, Wakamatsu T, Tsuyama A, Ogawa J, Matsumoto Y, et al. The impact of contact lens wear and visual display terminal work on ocular surface and tear functions in office workers. Am J Ophthalmol 2011;152:933-40.
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How to Cite
SHEKAR, N., GOWDA, D. V., KUMAR, H., JAIN, G. K., & JAIN, V. (2019). RECENT TRENDS IN MANAGEMENT OF KERATOCONJUNCTIVITIS SICCA (DRY EYE DISEASE). International Journal of Applied Pharmaceutics, 11(6), 30-36.
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