Comparison of Efficacy and Safety Evaluation of Latanoprost Formulations with and without Benzalkonium Chloride


Background: This study investigated the safety (cytotoxicity in vitro) and pharmacological effects (ocular hypotensive effects and aqueous humor concentrations in normotensive monkeys in vivo) of latanoprost formulations with benzalkonium chloride (latanoprost with BAK) and without BAK (NP). Methods: A bioequivalence study of latanoprost with BAK and NP was also conducted on human healthy volunteers. Cytotoxicity and the protective effect against H2O2 stress in vitro were evaluated using human corneal epithelial cells. The ocular hypotensive effects in normotensive monkeys were measured by pneumatonometer and the aqueous humor concentrations of latanoprost free acid were determined by liquid chromatography/mass spectrum (LC/MS) methods. The bioequivalence study of latanoprost with BAK and NP was carried out as a single eye drop, two-sequence, crossover randomized study. Results: Cytotoxicity tests in vitro revealed that NP was less toxic than latanoprost with BAK and significantly inhibited H2O2 induced cell damage while latanoprost with BAK did not. The hypotensive efficacy and the latanoprost free acid concentrations in aqueous humor of each formulation were not significantly different in monkeys. In the bioequivalence study, NP was bioequivalent to latanoprost with BAK. NP was safer than latanoprost with BAK with respect the results obtained in the in vitro cytotoxicity test. There was no difference observed between latanoprost with BAK and NP in the IOP lowering effect in monkeys and healthy volunteers. Conclusion: Taken together, these results indicate that NP is as effective as latanoprost with BAK, and is more likely to maintain ocular surface health than latanoprost with BAK.

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H. Kasai, Y. Aoyama, T. Kurasawa, T. Imamura, K. Tsuruma, H. Hara, H. Hirata and T. Yamamoto, "Comparison of Efficacy and Safety Evaluation of Latanoprost Formulations with and without Benzalkonium Chloride," Pharmacology & Pharmacy, Vol. 4 No. 4, 2013, pp. 377-384. doi: 10.4236/pp.2013.44054.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Iwase, Y. Suzuki, M. Araie, T. Yamamoto, H. Abe, S. Shirato, Y. Kuwayama, H. K. Mishima, H. Shimizu, G. Tomita, Y. Inoue and Y. Kitazawa, “The Prevalence of Primary Open-Angle Glaucoma in Japanese: The Tajimi Study,” Ophthalmology, Vol. 111, No. 9, 2004, pp. 16411648.
[2] Y Hotehama, H. K. Mishima, Y. Kitazawa and K. Masuda, “Ocular Hypotensive Effect of PhXA41 in Patients with Ocular Hypertension or Primary Open-Angle Glaucoma,” Japanese of Journal Ophthalmology, Vol. 37, No. 3, 1993, pp. 270-274.
[3] M. Diestelhorst, G. K. Krieglstein, M. Lusky and S. Nagasubramanian, “Clinical Dose-Regimen Studies with Latanoprost, a New Ocular Hypotensive PGF2 Alpha Analogue,” Survey of Ophthalmology, Vol. 41, Suppl. 2, 1997, pp. S77-S81. doi:10.1016/S0039-6257(97)80011-2
[4] K. Kashiwagi, T. Tsumura and S. Tsukahara, “LongTerm Effects of Latanoprost Monotherapy on Intraocular Pressure in Japanese Glaucoma Patients,” Journal of Glaucoma, Vol. 17, No. 8, 2008, pp. 662-666. doi:10.1097/IJG.0b013e318166656d
[5] K. Inoue, K. Okugawa, S. Kato, Y. Inoue, G. Tomita, T. Oshika and S. Amano, “Ocular Factors Relevant to AntiGlaucomatous Eyedrop-Related Keratoepitheliopathy,” Journal of Glaucoma, Vol. 12, No. 6, 2003, pp. 480-485. doi:10.1097/00061198-200312000-00007
[6] P. Baffa Ldo, J. R. Ricardo, A. C. Dias, C. M. Módulo, A. M. Braz, J. S. Paula, L. Rodrigues Mde and E. M. Roch, “Tear Film and Ocular Surface Alterations in Chronic Users of Antiglaucoma Medications,” Arquivos Brasileiros de Oftalmologia, Vol. 71, No. 1, 2008, pp. 18-21. doi:10.1590/S0004-27492008000100004
[7] N. Jaenen, C. Baudouin, P. Pouliquen, G. Manni, A. Figueiredo and T. Zeyen, ”Ocular Symptoms and Signs with Preserved and Preservative-Free Glaucoma Medications,” European Journal of Ophthalmology, Vol. 17, No. 3, 2007, pp. 341-349.
[8] J. Sarkar, S. Chaudhary, A. Namavari, O. Ozturk, J. K. Chang, L. Yco, S. Sonawane, V. Khanolkar, J. Hallak and S. Jain, “Corneal Neurotoxicity Due to Topical Benzalkonium Chloride,” Investigative of Ophthalmology and Visual Science, Vol. 53, No. 4, 2012, pp. 1792-1802. doi:10.1167/iovs.11-8775
[9] G. A. Georgiev, N. Yokoi, K. Koev, E. Kutsarova, S. Ivanova, A. Kyumurkov, A. Jordanova, R. Krastev and Z. Lalchev, “Surface Chemistry Study of the Interactions of Benzalkonium Chloride with Films of Meibum, Corneal Cells Lipids, and Whole Tears,” Investigative of Ophthalmology and Visual Science, Vol. 52, No. 7, 2011, 46454654. doi:10.1167/iovs.10-6271
[10] S. P. Epstein, M. Ahdoot, E. Marcus and P. A. Asbell, “Comparative Toxicity of Preservatives on Immortalized Corneal and Conjunctival Epithelial Cells,” Journal of Ocular Pharmacology and Therapeutics, Vol. 25, No. 2, 2009, pp. 113-119. doi:10.1089/jop.2008.0098
[11] A. M. Stevens, P. A. Kestelyn, D. De Bacquer and P. G. Kestelyn, “Benzalkonium Chloride Induces Anterior Chamber Inflammation in Previously Untreated Patients with Ocular Hypertension as Measured by Flare Meter: A Randomized Clinical Trial,” Acta Ophthalmologica, Vol. 90, No. 3, 2012, pp. e221-e224. doi:10.1111/j.1755-3768.2011.02338.x
[12] D. A. Ammar and M. Y. Kahook, “Effects of Benzalkonium Chlorideor Polyquad-Preserved Fixed Combination Glaucoma Medications on Human Trabecular Meshwork Cells,” Molecular Vision, Vol. 17, 2011, pp. 18061813.
[13] K. Miyake, N. Ibaraki, Y. Goto, S. Oogiya, J. Ishigaki, I. Ota and S. Miyake, “ESCRS Binkhorst Lecture 2002: Pseudophakic Preservative Maculopathy,” Journal of Cataract and Refractive Surgery, Vol. 29, No. 9, 2003, pp. 1800-1810. doi:10.1016/S0886-3350(03)00560-1
[14] R. Hackett and T. McDonald, “Eye Irritation,” In: F. Marzulli and H. Maibach, Eds., Advances in Modern Toxicology: Dermatoxicology, Hemisphere Publishing Corporation, Washington DC, 1991, pp. 749-815.
[15] Guideline for Bioequivalence Studies of Generic Products, 22 December 1997.
[16] K. Kashiwagi, “Changes in Trend of Newly Prescribed Anti-Glaucoma Medications in Recent Nine Years in a Japanese Local Community,” The Open Ophthalmology Journal, Vol. 28, No. 4, 2010, pp. 7-11. doi:10.2174/1874364101004010007
[17] E. P. O’Donoghue, “A Comparison of Latanoprost and Dorzolamide in Patients with Glaucoma and Ocular Hypertension: A 3 Month, Randomised Study. Ireland Latanoprost Study Group,” British Journal of Ophthalmology, Vol. 84, No. 6, 2000, pp. 579-582. doi:10.1136/bjo.84.6.579
[18] W. Y. Zhang, A. L. Po, H. S. Dua and A. Azuara-Blanco, “Meta-Analysis of Randomised Controlled Trials Comparing Latanoprost with Timolol in the Treatment of Patients with Open Angle Glaucoma or Ocular Hypertension,” British Journal of Ophthalmology, Vol. 85, No. 8, 2001, pp. 983-990. doi:10.1136/bjo.85.8.983
[19] H. Tsukamoto, H. K. Mishima, Y. Kitazawa, M. Araie, H. Abe and A. Negi (Glaucoma Study Group), “A Comparative Clinical Study of Latanoprost and Isopropyl Unoprostone in Japanese Patients with Primary Open-Angle Glaucoma and Ocular Hypertension,” Journal of Glaucoma, Vol. 11, No. 6, 2002, pp. 497-501. doi:10.1097/00061198-200212000-00008
[20] P. T. Che, T. Aung, M. V. Aquino and P. Rojanapongpun (EXACT Study Group), “Intraocular Pressure-Reducing Effects and Safety of Latanoprost versus Timolol in Patients with Chronic Angle-Closure Glaucoma,” Ophthalmology, Vol. 111, No. 3, 2004, pp. 427-434. doi:10.1016/j.ophtha.2003.06.007
[21] P. Denis, C. Baudouin, A. Bron, J. P. Nordmann, J. P. Renar, J. F. Rouland, E. Sellem and M. Amrane, “FirstLine Latanoprost Therapy in Ocular Hypertension or Open-Angle Glaucoma Patients: A 3-Month Efficacy Analysis Stratified by Initial Intraocular Pressure,” BMC Ophthalmology, Vol. 10, 2010, p. 4. doi:10.1186/1471-2415-10-4
[22] C. Baudouin, A. Labbé, H. Liang, A. Pauly and F. Brignole-Baudouin, “Preservatives in Eyedrops: The Good, the Bad and the Ugly,” Progress in Retinal and Eye Research, Vol. 29, No. 4, 2010, pp. 312-334. doi:10.1016/j.preteyeres.2010.03.001
[23] S. K. Mirza and S. M. Johnson, “Efficacy and Patient Tolerability of Travoprost BAK-Free Solution in Patients with Open-Angle Glaucoma and Ocular Hypertension,” Clinical Ophthalmology, Vol. 4, 2010, pp. 877-888. doi:10.2147/OPTH.S6292
[24] G. Katz, C. L. Springs, E. R. Craven and M. Montecchi-Palmer, “Ocular Surface Disease in Patients with Glaucoma or Ocular Hypertension Treated with Either BAK-Preserved Latanoprost or BAK-Free Travoprost,” Clinical Ophthalmology, Vol. 4, 2010, pp. 1253-1261. doi:10.2147/OPTH.S14113
[25] M. J. Miyashiro, S. C. Lo, J. A. Stewart and W. C. Stewart, “Efficacy, Safety, and Tolerability of Travoprost 0.004% BAK-Free versus Prior Treatment with Latanoprost 0.005% in Japanese Patients,” Clinical Ophthalmology, Vol. 4, 2010, pp. 1355-1359. doi:10.2147/OPTH.S13460
[26] A. Hommer, “A Review of Preserved and PreservativeFree Prostaglandin Analogues for the Treatment of OpenAngle Glaucoma and Ocular Hypertension,” Drugs of Today (Barcelona), Vol. 46, No. 6, 2010, pp. 409-416. doi:10.1358/dot.2010.46.6.1482107
[27] C. Baudouin, L. Riancho, J. M. Warnet and F. Brignole, “In Vitro Studies of Antiglaucomatous Prostaglandin Analogues: Travoprost with and without Benzalkonium Chloride and Preserved Latanoprost,” Investigative of Ophthalmology and Visual Science, Vol. 48, No. 9, 2007, pp. 4123-4128. doi:10.1167/iovs.07-0266
[28] M. Ayaki, A. Iwasawa and Y. Inoue, “Toxicity of Antiglaucoma Drugs with and without Benzalkonium Chloride to Cultured Human Corneal Endothelial Cells,” Clinical Ophthalmology, Vol. 4, 2010, pp. 1217-1222. doi:10.2147/OPTH.S13708
[29] H. Liang, A. Pauly, L. Riancho, C. Baudouin and F. Brignole-Baudouin, “Toxicological Evaluation of PreservativeContaining and Preservative-Free Topical Prostaglandin Analogues on a Three-Dimensional-Reconstituted Corneal Epithelium System,” British Journal of Ophthalmology, Vol. 95, No. 6, 2011, pp. 869-875. doi:10.1136/bjo.2010.189449
[30] S. Nakagawa, T. Usui, S. Yokoo, S. Omichi, M. Kimakura, Y. Mori, K. Miyata, M. Aihara, S. Amano and M. Araie, “Toxicity Evaluation of Antiglaucoma Drugs Using Stratified Human Cultivated Corneal Epithelial Sheets,” Investigative of Ophthalmology and Visual Science, Vol. 53, No. 9, 2012, pp. 5154-5160. doi:10.1167/iovs.12-9685
[31] J. M. Guenoun, C. Baudouin, P. Rat, A. Pauly, J. M. Warnet and F. Brignole-Baudouin, “In Vitro Comparison of Cytoprotective and Antioxidative Effects of Latanoprost, Travoprost, and Bimatoprost on Conjunctiva-Derived Epithelial Cells,” Investigative of Ophthalmology and Visual Science, Vol. 46, No. 12, 2005, pp. 4594-4549. doi:10.1167/iovs.05-0776
[32] A. L. Yu, R. Fuchshofer, A. Kampik and U. Welge-Lüssen, “Effects of Oxidative Stress in Trabecular Meshwork Cells Are Reduced by Prostaglandin Analogues,” Investigative of Ophthalmology and Visual Science, Vol. 49, No. 11, 2008, pp. 4872-4880. doi:10.1167/iovs.07-0984
[33] K. Inoue, M. Masumoto, M. Wakakura and G. Tomita, “Ocular Hypotensive Effects and Safety Latanoprost without Benzalkonium,” Journal of the Eye, Vol. 28, No. 11, 2011, pp. 1635-1639.

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