In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac

Walters, Tom; Raizman, Michael B.; Ernest, Paul; Gayton, Johnny L.; Lehmann, Robert

doi:10.1016/j.jcrs.2007.05.015

Cited by 103 publications

(104 citation statements)

References 23 publications

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“…The drug concentrations in the aqueous humour were compared after topical application with those obtained after intracameral injection of an equivalent dose of 0.25 mg of ketorolac tromethamine per eye using 14C (Ling & Combas, 1987;Walters et al, 2007). Such factors have prompted research for the development of a more safe and effective KT formulations (Schoenwald, 1985;Sinha et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies

Fathalla

Vangala

Longman

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

129

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, Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies, European Journal of Pharmaceutics and Biopharmaceutics (2017), doi: http://dx.doi.org/10. 1016/j.ejpb.2017.01.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThis study was aimed at preparing, characterising and evaluating in situ gel formulations based on a blend of two hydrophilic polymers i.e. poloxamer 407 (P407) and poloxamer 188 (P188) for a sustained ocular delivery of ketorolac tromethamine (KT). Drug-polymer interaction studies were performed using DSC and FT-IR. The gelation temperature (T sol-gel ), gelation time, rheological behaviour, mucoadhesive characteristics of these gels, transcorneal permeation and ocular irritation as well as toxicity was investigated. DSC and FT-IR studies revealed that there may be electrostatic interactions between the drug and the polymers used.P188 modified the T sol/gel of P407 bringing it close to eye temperature (35 o C) compared with the formulation containing P407 alone. Moreover, gels that comprised P407 and P188 exhibited a pseudoplastic behaviour at different concentrations. Furthermore, mucoadhesion study using mucin discs showed that in situ gel formulations have good mucoadhesive characteristics upon increasing the concentration of P407. When comparing formulations PP11 and PP12, the work of adhesion decreased significantly (P < 0.001) from 377.9 ± 7.79 mN.mm to 272.3 ± 6.11 mN.mm. In vitro release and ex vivo permeation experiments indicated that the in situ gels were able to prolong and control KT release as only 48% of the KT released within 12 h. In addition, the HET-CAM and BCOP tests confirmed the nonirritancy of KT loaded in situ gels, and HET-CAM test demonstrated the ability of ocular protection against strongly irritant substances. MTT assay on primary corneal epithelial cells revealed that in situ gel formulations loaded with KT showed reasonable and acceptable percent cell viability compared with control samples.

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Section: Introductionmentioning

confidence: 99%

Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies

Fathalla

Vangala

Longman

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

129

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“…It has superior corneal penetration compared to other NSAIDs and is bio activated by ocular tissues to amfenac. (13,19) Several studies have measured aqueous levels of NSAIDs in humans after topical use. After a single application, peak aqueous drug levels are detectable for nepafenac 0.1% (205.3 ng/mL; peak 30 minutes).…”

Section: Discussionmentioning

confidence: 99%

“…After a single application, peak aqueous drug levels are detectable for nepafenac 0.1% (205.3 ng/mL; peak 30 minutes). (13) In contrast to aqueous drug levels, there is a paucity of human studies measuring NSAID levels in the vitreous after topical application. A single study measured vitreous drug levels in patients who received ketorolac 0.4% four times daily, bromfenac 0.09% two times daily, or nepafenac 0.1% three times daily for three days before vitrectomy surgery.…”

Section: Discussionmentioning

confidence: 99%

“…In ophthalmology, topical NSAIDs are used to stabilize pupillary dilation during intraocular surgery and to treat allergic conjunctivitis and postoperative inflammation, pain and cystoid macular edema (CME). (12)(13)(14)(15)(16)(17) If an NSAID can penetrate to the retina, it could possibly reduce vascular permeability by inhibiting the inflammatory cascade. Based on this hypothesis, patients with DME may benefit from topical nepafenac 0.1% in an attempt to reduce the edema and improve vision.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Study of Intravitreal Ranibizumab with and Without Nepafenac Eye Drops for Center Involving Diabetic Macular Edema

Shousha¹,

Helaly²

2015

jmscr

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“…12 A multicentre investigative study evaluating the aqueous humour concentrations and COX inhibitory activities of nepafenac, amfenac, ketorolac and bromfenac following topical ocular administration in patients having cataract surgery, found that nepafenac had greater ocular bioavailability than any other drug tested (see Figure 3). 13 Nepafenac had the shortest time to peak concentration and greatest peak aqueous humour concentration. Additionally, both the C max and the area under the curve (AUC) of nepafenac were significantly larger than the other drugs tested (P<0.05).…”

mentioning

confidence: 93%

Nepafenac in the Prevention and Treatment of Ocular Inflammation and Pain Following Cataract Surgery and in the Prevention of Post-operative Macular Oedema in Diabetic Patients

Nardi¹

2012

European Ophthalmic Review

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Nepafenac ophthalmic suspension is a topical non-steroidal anti-inflammatory drug (NSAID) approved in the US and Europe for prevention and treatment of post-operative pain and inflammation associated with cataract surgery, and recently approved in Europe for reduction in risk of post-operative macular oedema associated with cataract surgery in diabetic patients. Unlike conventional NSAIDs, nepafenac is a prodrug that is uncharged and this results in great corneal permeability. Experimental studies on nepafenac demonstrated enhanced permeability compared with other NSAIDs, and rapid bioactivation to amfenac by intraocular hydrolases within ocular tissues including ciliary body epithelium, retina, choroid and cornea, which results in targeted delivery of active drug to anterior and posterior segments.Furthermore, these study results have been confirmed in clinical trials. Nepafenac may have prolonged activity in vascularised tissues of the eye because bioconversion is targeted to the iris/ciliary body, and to a greater extent the retina and choroid. Nepafenac and amfenac are potent inhibitors of cyclo-oxygenase (COX) enzyme isoforms, COX-1 and COX-2. Topical nepafenac penetrated into the posterior segment in a rabbit model of concanavalin-A induced retinal inflammation, where it diminished vitreous protein and prostaglandin E 2 concentrations and reduced breakdown of the blood-retinal barrier. Other NSAIDs, including ketorolac, failed to reduce the increase of these inflammatory markers in the same study. A randomised clinical study showed that based on retinal thickening and vision, treatment with nepafenac beginning pre-surgery and used for up to 90 days post-cataract surgery is effective in preventing macular oedema and associated loss of visual acuity in diabetic patients. KeywordsNon-steroidal anti-inflammatory drugs (NSAIDs), cataract surgery, pain, inflammation, nepafenac, prodrug, permeability Disclosure: Marco Nardi has participated in the European registration study of nepafenac and has given presentations on this for which he has received honoraria. Acknowledgement:Writing support was provided by Touch Briefings.

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In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac

Abstract: Nepafenac showed significantly greater ocular bioavailability and amfenac demonstrated greater potency at COX-2 inhibition than ketorolac or bromfenac.

Cited by 103 publications

References 23 publications

Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies

Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies

Comparative Study of Intravitreal Ranibizumab with and Without Nepafenac Eye Drops for Center Involving Diabetic Macular Edema

Nepafenac in the Prevention and Treatment of Ocular Inflammation and Pain Following Cataract Surgery and in the Prevention of Post-operative Macular Oedema in Diabetic Patients

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