The ocular distribution of (14)C-labeled bromfenac ophthalmic solution 0.07% in a rabbit model

George A Baklayan, Mauricio Muñoz, George A Baklayan, Mauricio Muñoz

Abstract

Purpose: To evaluate the ocular distribution of an advanced formulation of bromfenac ophthalmic solution. Two studies were conducted in rabbits: 1) a 12-hour parallel-group study comparing the ocular distribution of (14)C-bromfenac ophthalmic solution 0.07%, pH 7.8 with that of (14)C-bromfenac ophthalmic solution 0.09%, pH 8.3, and 2) a 24-hour study evaluating the ocular distribution of (14)C-bromfenac ophthalmic solution 0.07%, pH 7.8.

Methods: In the 12-hour study, rabbits were randomized to receive 50 μL of (14)C-bromfenac 0.07%, pH 7.8 or 50 μL (14)C-bromfenac 0.09%, pH 8.3 in one eye, whereas, in the 24-hour, study both eyes received 50 μL of (14)C-bromfenac 0.07%, pH 7.8. Ocular tissues were collected at 1, 2, 4, 8, 12 (both studies) and 24 hours (second study only) following drug instillation, and tissue radioactivity was determined using liquid scintillation chromatography.

Results: Measureable levels of bromfenac were observed in all ocular tissues, with the exception of vitreous humor, regardless of formulation. In the 12-hour study, high concentrations of (14)C-bromfenac were found in the sclera, followed by the iris/ciliary body, aqueous humor, choroid, retina, and lens. There was no significant difference between the bromfenac 0.07%, pH 7.8 and bromfenac 0.09%, pH 8.3 formulations in any (14)C-bromfenac tissue levels at any time point, with the exception of in sclera at 2 hours post-instillation (0.451 μg eq/g versus 0.302 μg eq/g, respectively, P<0.001). There was also no significant difference in the total amount of (14)C-bromfenac in the tissues evaluated following instillation of the two formulations. In the 24-hour study evaluating bromfenac 0.07%, pH 7.8 only, high concentrations of (14)C-bromfenac were found 1 hour post-instillation in the cornea (2.402 μg eq/g) and conjunctiva (1.049 μg eq/g), two tissues not evaluated in the 12-hour study. The rank order of (14)C-bromfenac levels in the other ocular tissues was the same as that observed in the 12-hour study, with measureable amounts of (14)C-bromfenac detected through 24 hours in all tissues with the exception of vitreous humor.

Conclusion: Bromfenac ophthalmic solution 0.07%, pH 7.8 readily penetrated ocular tissues with levels similar to those of bromfenac ophthalmic solution 0.09%, pH 8.3.

Keywords: eye; pH; penetration; pharmacokinetics; topical NSAIDs.

Figures

Figure 1
Figure 1
Molecular structure of bromfenac showing the position of the 14C label. Note: *14C.
Figure 2
Figure 2
Ocular distribution of 14C-bromfenac in rabbits over 12 hours following topical administration of 14C-bromfenac 0.07%, pH 7.8 (A) or 14C-bromfenac 0.09%, pH 8.3 (B).
Figure 3
Figure 3
Ocular distribution of 14C-bromfenac in rabbits over 24 hours following topical administration of 14C-bromfenac 0.07%, pH 7.8.

References

    1. Bucolo C, Melilli B, Piazza C, Zurria M, Drago F. Ocular pharmacokinetics profile of different indomethacin topical formulations. J Ocul Pharmacol Ther. 2011;27(6):571–576.
    1. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin. 1992;10(3):505–512.
    1. Becker B. The side effects of corticosteroids. Invest Ophthalmol. 1964;3:492–497.
    1. McGhee CN. Pharmacokinetics of ophthalmic corticosteroids. Br J Ophthalmol. 1992;76:681–684.
    1. Miyanaga M, Miyai T, Nejima R, Maruyama Y, Miyata K, Kato S. Effect of bromfenac ophthalmic solution on ocular inflammation following cataract surgery. Acta Ophthalmol. 2009;87(3):300–305.
    1. Prolensa® [package insert] Tampa, FL: Bausch + Lomb; 2013.
    1. Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical ocular delivery of NSAIDs. AAPS J. 2008;10(2):229–241.
    1. Guex-Crosier Y. Non-steroidal anti-inflammatory drugs and ocular inflammation. Klin Monbl Augenheilkd. 2001;218(5):305–308. French.
    1. Gluud BS, Jensen OL, Krogh E, Birgens HS. Prostaglandin E2 level in tears during postoperative inflammation of the eye. Acta Ophthalmol (Copenh) 1985;63(4):375–379.
    1. Oka T, Shearer T, Azuma M. Involvement of cyclooxygenase-2 in rat models of conjunctivitis. Curr Eye Res. 2004;29(1):27–34.
    1. Miyamoto T, Saika S, Okada Y, et al. Expression of cyclooxygenase-2 in corneal cells after photorefractive keratectomy and laser in situ keratomileusis in rabbits. J Cataract Refract Surg. 2004;30(12):2612–2617.
    1. Radi ZA, Render JA. The pathophysiologic role of cyclo-oxygenases in the eye. J Ocul Pharmacol Ther. 2008;24(2):141–151.
    1. Walsh DA, Moran HW, Shamblee DA, et al. Antiinflammatory agents. 3. Synthesis and pharmacological evaluation of 2-amino-3-benzoylphenylacetic acid and analogues. J Med Chem. 1984;27(11):1379–1388.
    1. Yanni JM, Graff G, Hellberg MR, inventors, Alcon Laboratories Inc., assignee Adminstering 3-benzoylphenylacetamide derivatives. 1995. Dec 12, United States patent US5475034.
    1. Ruiz J, López M, Milà J, Lozoya E, Lozano JJ, Pouplana R. QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues. J Comput Aided Mol Des. 1993;7(2):183–198.
    1. Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin. 2006;22(6):1133–1140.
    1. Bucolo C, Marrazzo G, Platania CB, Romano GL, Drago F, Salomone S. Effects of topical indomethacin, bromfenac and nepafenac on lipopolysaccharide-induced ocular inflammation. J Pharm Pharmacol. 2014;66(7):954–960.
    1. Miyake K, Ogawa T, Tajika T, Gow JA, McNamara TR. Ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1% in human aqueous humor. J Ocul Pharmacol Ther. 2008;24(6):573–578.
    1. Baklayan GA, Patterson HM, Song CK, Gow JA, McNamara TR. 24-hour evaluation of the ocular distribution of (14)C-labeled bromfenac following topical instillation into the eyes of New Zealand White rabbits. J Ocul Pharmacol Ther. 2008;24(4):392–398.
    1. Kida T, Ogawa T, McNamara TR, Song CK, Gow JA. Evaluation of the human Cox-2 inhibition of amfenac, bromfenac, diclofenac, and ketorolac; Proceedings of the Annual American Society of Cataract and Refractive Surgery Conference; April 27 – May 2, 2007; San Diego, CA.
    1. Ueda K, Ohtori A, Tojo K. Effects of pathological conditions on ocular pharmacokinetics of antimicrobial drugs. Chem Pharm Bull (Tokyo) 2010;58(10):1301–1305.
    1. Cho H, Mozayan A. New look at ocular inflammation control – powerful and fast-acting twice-daily bromfenac for a novel standard in the treatment of inflammation. European Ophthalmic Review. 2011;5(1):20–26.
    1. O’Brien TP. Emerging guidelines for the use of NSAID therapy to optimize cataract surgery patient care. Curr Med Res Opin. 2005;21(7):1131–1137.
    1. Jones J, Francis P. Ophthalmic utility of topical bromfenac, a twice-daily nonsteroidal anti-inflammatory agent. Expert Opin Pharmacother. 2009;10(14):2379–2385.
    1. Carreño E, Portero A, Galarreta DJ, Herreras JM. Update on twice-daily bromfenac sodium sesquihydrate to treat postoperative ocular inflammation following cataract extraction. Clin Ophthalmol. 2012;6:637–644.
    1. Cable M. Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. Clin Ophthalmol. 2012;6:997–1004.
    1. Warren KA, Bahrani H, Fox JE. NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema. Retina. 2010;30:260–266.
    1. Radwan AE, Arcinue CA, Yang P, Artornsombudh P, Abu Al-Fadl EM, Foster CS. Bromfenac alone or with single intravitreal injection of bevacizumab or triamcinolone acetonide for treatment of uveitic macular edema. Graefes Arch Clin Exp Ophthalmol. 2013;251:1801–1806.
    1. Endo N, Kato S, Haruyama K, Shoji M, Kitano S. Efficacy of bromfenac sodium ophthalmic solution in preventing cystoid macular oedema after cataract surgery in patients with diabetes. Acta Ophthalmol. 2010;88(8):896–900.
    1. Wang QW, Yao K, Xu W, et al. Bromfenac sodium 0.1%, fluorometholone 0.1% and dexamethasone 0.1% for control of ocular inflammation and prevention of cystoid macular edema after phacoemulsification. Ophthalmologica. 2013;229(4):187–194.
    1. Gomi F, Sawa M, Tsujikawa M, Nishida K. Topical bromfenac as an adjunctive treatment with intravitreal ranibizumab for exudative age-related macular degeneration. Retina. 2012;32:1804–1810.
    1. Flaxel C, Schain MB, Hamon SC, Francis PJ. Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration: a pilot study. Retina. 2012;32:417–423.
    1. Zweifel SA, Engelbert M, Khan S, Freund KB. Retrospective review of the efficacy of topical bromfenac (0.09%) as an adjunctive therapy for patients with neovascular age-related macular degeneration. Retina. 2009;29:1527–1531.

Source: PubMed

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