{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T21:15:35Z","timestamp":1779311735223,"version":"3.51.4"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T00:00:00Z","timestamp":1553212800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drug Deliv. and Transl. Res."],"published-print":{"date-parts":[[2019,10]]},"DOI":"10.1007\/s13346-018-00614-x","type":"journal-article","created":{"date-parts":[[2019,3,22]],"date-time":"2019-03-22T15:03:27Z","timestamp":1553267007000},"page":"867-878","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effect of formulation parameters on pharmacokinetics, pharmacodynamics, and safety of diclofenac nanomedicine"],"prefix":"10.1007","volume":"9","author":[{"given":"Dhanya","family":"Narayanan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gopikrishna J.","family":"Pillai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shantikumar V.","family":"Nair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepthy","family":"Menon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,3,22]]},"reference":[{"key":"614_CR1","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1163\/156856005774415565","volume":"13","author":"WF Kean","year":"2005","unstructured":"Kean WF, Buchanan WW. The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacology. 2005;13:343\u201370.","journal-title":"Inflammopharmacology"},{"key":"614_CR2","first-page":"18","volume":"56","author":"G Singh","year":"1999","unstructured":"Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18\u201324.","journal-title":"J Rheumatol Suppl"},{"key":"614_CR3","first-page":"135","volume":"323","author":"J Carson","year":"1989","unstructured":"Carson J, Notis WM, Orris ES. Colonic ulceration and bleeding during diclofenac therapy. N Engl J Med. 1989;323:135\u20137.","journal-title":"N Engl J Med"},{"key":"614_CR4","doi-asserted-by":"publisher","first-page":"7563","DOI":"10.1073\/pnas.96.13.7563","volume":"96","author":"TD Warner","year":"1999","unstructured":"Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96:7563\u20138.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"614_CR5","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/BF00568201","volume":"16","author":"JV Willis","year":"1979","unstructured":"Willis JV, Kendall MJ, Flinn RM, Thornhill DP, Welling PG. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol. 1979;16:405\u201310.","journal-title":"Eur J Clin Pharmacol"},{"key":"614_CR6","doi-asserted-by":"publisher","first-page":"e1001098","DOI":"10.1371\/journal.pmed.1001098","volume":"8","author":"P McGettigan","year":"2011","unstructured":"McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8:e1001098.","journal-title":"PLoS Med"},{"key":"614_CR7","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3109\/00365598909180832","volume":"23","author":"AC Kinn","year":"1989","unstructured":"Kinn AC, Elbarouni J, Seideman P, Sollevi A. The effect of diclofenac sodium on renal function. Scand J Urol Nephrol. 1989;23:153\u20137.","journal-title":"Scand J Urol Nephrol"},{"key":"614_CR8","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1586\/ecp.10.120","volume":"3","author":"KM Knights","year":"2010","unstructured":"Knights KM, Mangoni AA, Miners JO. Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity. Expert Rev Clin Pharmacol. 2010;3:769\u201376.","journal-title":"Expert Rev Clin Pharmacol"},{"key":"614_CR9","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/sj.clpt.6100400","volume":"83","author":"L Zhang","year":"2008","unstructured":"Zhang L. Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther. 2008;83:761\u20139.","journal-title":"Clin Pharmacol Ther"},{"key":"614_CR10","first-page":"283","volume":"53","author":"SM Moghimi","year":"2001","unstructured":"Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53:283\u2013318.","journal-title":"Pharmacol Rev"},{"key":"614_CR11","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1016\/j.addr.2006.09.011","volume":"58","author":"OC Farokhzad","year":"2006","unstructured":"Farokhzad OC, Langer R. Nanomedicine: developing smarter therapeutic and diagnostic modalities. Adv Drug Deliv Rev. 2006;58:1456\u20139.","journal-title":"Adv Drug Deliv Rev"},{"key":"614_CR12","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1016\/S1359-6446(05)03654-8","volume":"10","author":"C Shaffer","year":"2005","unstructured":"Shaffer C. Nanomedicine transforms drug delivery. Drug Discov Today. 2005;10:1581\u20132.","journal-title":"Drug Discov Today"},{"key":"614_CR13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.urolonc.2007.03.017","volume":"26","author":"F Alexis","year":"2008","unstructured":"Alexis F. New frontiers in nanotechnology for cancer treatment. Urol Oncol Semin Orig Investig. 2008;26:74\u201385.","journal-title":"Urol Oncol Semin Orig Investig"},{"key":"614_CR14","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.ijbiomac.2014.12.012","volume":"74","author":"D Narayanan","year":"2015","unstructured":"Narayanan D, Nair SV, Menon D. A systematic evaluation of hydroxyethyl starch as a potential nanocarrier for parenteral drug delivery. Int J Biol Macromol. 2015;74:575\u201384.","journal-title":"Int J Biol Macromol"},{"key":"614_CR15","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1007\/s11051-017-3968-6","volume":"19","author":"AP Duarte Junior","year":"2017","unstructured":"Duarte Junior AP, Tavares EJM, Alves TVG, de Moura MR, da Costa CEF, Silva J\u00fanior JOC, et al. Chitosan nanoparticles as a modified diclofenac drug release system. J Nanopart Res. 2017;19:274. \n                    https:\/\/doi.org\/10.1007\/s11051-017-3968-6\n                    \n                  .","journal-title":"J Nanopart Res"},{"key":"614_CR16","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.2042-7158.2012.01587.x","volume":"65","author":"S El-Sousi","year":"2013","unstructured":"El-Sousi S, Nacher A, Mura C, Catalan-Latorre A, Merino V. Hydroxypropylmethylcellulose films for the ophthalmic delivery of diclofenac sodium. J Pharm Pharmacol. 2013;65:193\u2013200.","journal-title":"J Pharm Pharmacol"},{"key":"614_CR17","doi-asserted-by":"publisher","first-page":"726","DOI":"10.3109\/02652048.2010.513456","volume":"27","author":"D Liu","year":"2010","unstructured":"Liu D, Ge Y, Tang Y, Yuan Y, Zhang Q. Solid lipid nanoparticles for transdermal delivery of diclofenac sodium: preparation, characterization and in vitro studies. J Microencapsul. 2010;27:726\u201334.","journal-title":"J Microencapsul"},{"key":"614_CR18","first-page":"120","volume":"42","author":"BL Seth","year":"1992","unstructured":"Seth BL. Comparative pharmacokinetics and bioavailability study of percutaneous absorption of diclofenac from two topical formulations containing drug as a solution gel or as an emulsion gel. Arzneimittelforschung. 1992;42:120\u20132.","journal-title":"Arzneimittelforschung"},{"key":"614_CR19","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1016\/j.nano.2011.12.006","volume":"8","author":"P Kandadi","year":"2012","unstructured":"Kandadi P, Syed MA, Goparaboina S, Veerabrahma K. Albumin coupled lipid nanoemulsions of diclofenac for targeted delivery to inflammation. Nanomedicine. 2012;8:1162\u201371.","journal-title":"Nanomedicine"},{"key":"614_CR20","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/smll.200800003","volume":"5","author":"ML Schipper","year":"2009","unstructured":"Schipper ML, Iyer G, Koh AL, Cheng Z, Ebenstein Y, Aharoni A, et al. Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small. 2009;5:126\u201334.","journal-title":"Small"},{"key":"614_CR21","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1016\/S1359-6446(05)03575-0","volume":"10","author":"FM Veronese","year":"2005","unstructured":"Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451\u20138.","journal-title":"Drug Discov Today"},{"key":"614_CR22","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.nano.2009.02.002","volume":"5","author":"J Park","year":"2009","unstructured":"Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, et al. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine. 2009;5:410\u20138.","journal-title":"Nanomedicine"},{"key":"614_CR23","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1016\/j.nano.2013.02.001","volume":"9","author":"D Narayanan","year":"2013","unstructured":"Narayanan D, M.G. G, H. L, Koyakutty M, Nair S, Menon D. Poly-(ethylene glycol) modified gelatin nanoparticles for sustained delivery of the anti-inflammatory drug ibuprofen-sodium: an in vitro and in vivo analysis. Nanomedicine. 2013;9:818\u201328.","journal-title":"Nanomedicine"},{"key":"614_CR24","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1021\/mp800051m","volume":"5","author":"F Alexis","year":"2008","unstructured":"Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5:505\u201315.","journal-title":"Mol Pharm"},{"key":"614_CR25","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/j.colsurfb.2015.10.047","volume":"136","author":"GJ Pillai","year":"2015","unstructured":"Pillai GJ, Greeshma MM, Menon D. Impact of poly (lactic-co-glycolic acid) nanoparticle surface charge on protein, cellular and haematological interactions. Colloids Surf B: Biointerfaces. 2015;136:1058\u201366.","journal-title":"Colloids Surf B: Biointerfaces"},{"key":"614_CR26","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0168-3659(01)00451-5","volume":"77","author":"Y Yamamoto","year":"2001","unstructured":"Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K. Long-circulating poly (ethylene glycol)-poly(D,L-lactide) block copolymer micelles with modulated surface charge. J Control Release. 2001;77:27\u201338.","journal-title":"J Control Release"},{"key":"614_CR27","first-page":"77","volume":"2","author":"G Singhvi","year":"2011","unstructured":"Singhvi G, Singh M. In vitro drug release characterization models. Int J Pharm Stud Res. 2011;2:77\u201384.","journal-title":"Int J Pharm Stud Res"},{"key":"614_CR28","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1111\/j.1365-2621.2003.tb07032.x","volume":"68","author":"A Chaovanalikit","year":"2003","unstructured":"Chaovanalikit A, Dougherty MP, Camire ME, Briggs J. Ascorbic acid fortification reduces anthocyanins in extruded blueberry-corn cereals. J Food Sci. 2003;68:2136\u201340.","journal-title":"J Food Sci"},{"key":"614_CR29","first-page":"65","volume":"288","author":"R Bort","year":"1999","unstructured":"Bort R, Ponsoda X, Jover R, G\u00f3mez-Lech\u00f3n MJ, Castell JV. Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J Pharmacol Exp Ther. 1999;288:65\u201372.","journal-title":"J Pharmacol Exp Ther"},{"key":"614_CR30","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1126\/science.1114397","volume":"311","author":"A Nel","year":"2006","unstructured":"Nel A. Toxic potential of materials at the nanolevel. Science. 2006;311:622\u20137.","journal-title":"Science"},{"key":"614_CR31","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.1016\/j.biomaterials.2010.01.065","volume":"31","author":"C He","year":"2010","unstructured":"He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657\u201366.","journal-title":"Biomaterials"},{"key":"614_CR32","unstructured":"International Pharmaceutical Excipients Council. The IPEC excipient information package (EIP): template and user guide. Brussels: IPEC; 2009."},{"key":"614_CR33","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s11094-009-0265-4","volume":"43","author":"GN Aleeva","year":"2009","unstructured":"Aleeva GN, et al. The role of excipients in determining the pharmaceutical and therapeutic properties of medicinal agents. Pharm Chem J. 2009;43:51\u20136.","journal-title":"Pharm Chem J"},{"key":"614_CR34","first-page":"21","volume":"1","author":"SP Chaudhari","year":"2012","unstructured":"Chaudhari SP, Patil PS. Pharmaceutical excipients: a review. Int J Adv Pharm Biol Chem. 2012;1:21\u201334.","journal-title":"Int J Adv Pharm Biol Chem"},{"key":"614_CR35","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.jconrel.2011.09.098","volume":"161","author":"N Bertrand","year":"2012","unstructured":"Bertrand N, Leroux J. The journey of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release. 2012;161:152\u201363.","journal-title":"J Control Release"},{"key":"614_CR36","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1073\/pnas.1010013108","volume":"108","author":"TJ Merkel","year":"2011","unstructured":"Merkel TJ, Jones SW, Herlihy KP, Kersey FR, Shields AR, Napier M, et al. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc Natl Acad Sci. 2011;108:586\u201391.","journal-title":"Proc Natl Acad Sci"},{"key":"614_CR37","doi-asserted-by":"publisher","first-page":"10640","DOI":"10.1021\/ja039651w","volume":"126","author":"R Kumar","year":"2004","unstructured":"Kumar R, Chen MH, Parmar VS, Samuelson LA, Kumar J, Nicolosi R, et al. Supramolecular assemblies based on copolymers of PEG600 and functionalized aromatic diesters for drug delivery applications. J Am Chem Soc. 2004;126:10640\u20134.","journal-title":"J Am Chem Soc"},{"key":"614_CR38","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.ijpharm.2012.03.055","volume":"430","author":"SY Tang","year":"2012","unstructured":"Tang SY, Sivakumar M, Ng AM-H, Shridharan P. Anti-inflammatory and analgesic activity of novel oral aspirin-loaded nanoemulsion and nano multiple emulsion formulations generated using ultrasound cavitation. Int J Pharm. 2012;430:299\u2013306.","journal-title":"Int J Pharm"},{"key":"614_CR39","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.surg.2010.01.001","volume":"148","author":"MR Hemmila","year":"2010","unstructured":"Hemmila MR, Mattar A, Taddonio MA, Arbabi S, Hamouda T, Ward PA, et al. Topical nanoemulsion therapy reduces bacterial wound infection and inflammation after burn injury. Surgery. 2010;148:499\u2013509.","journal-title":"Surgery"},{"key":"614_CR40","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.mehy.2013.08.007","volume":"81","author":"V Garg","year":"2013","unstructured":"Garg V, Jain GK, Nirmal J, Kohli K. Topical tacrolimus nanoemulsion, a promising therapeutic approach for uveitis. Med Hypotheses. 2013;81:901\u20134.","journal-title":"Med Hypotheses"},{"key":"614_CR41","unstructured":"Food and Drug Administration. Single dose acute toxicity testing for pharmaceuticals. Fed Regist. 1996;61:43934."},{"key":"614_CR42","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1093\/bja\/62.5.545","volume":"62","author":"WI Campbell","year":"1989","unstructured":"Campbell WI, Watters CH. Venous sequelae following i.v. administration of diclofenac. Br J Anaesthol. 1989;62:545\u20137.","journal-title":"Br J Anaesthol"},{"key":"614_CR43","doi-asserted-by":"publisher","first-page":"13S","DOI":"10.1016\/S0002-9343(98)00070-9","volume":"105","author":"KG Tolman","year":"2015","unstructured":"Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med. 2015;105:13S\u20139S.","journal-title":"Am J Med"},{"key":"614_CR44","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3109\/03009749609097226","volume":"25","author":"JR Vane","year":"1996","unstructured":"Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol. 1996;25:9\u201321.","journal-title":"Scand J Rheumatol"},{"key":"614_CR45","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1023\/A:1007443610025","volume":"13","author":"X Ponsoda","year":"1997","unstructured":"Ponsoda X, et al. The use of cultured hepatocytes to investigate the mechanisms of drug hepatotoxicity. Cell Biol Toxicol. 1997;13:331\u20138.","journal-title":"Cell Biol Toxicol"},{"key":"614_CR46","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1006\/taap.1993.1097","volume":"120","author":"A Kretzrommel","year":"1993","unstructured":"Kretzrommel A, Boelsterli UA. Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes. Toxicol Appl Pharmacol. 1993;120:155\u201361.","journal-title":"Toxicol Appl Pharmacol"},{"key":"614_CR47","first-page":"123","volume":"7","author":"ZK El-Ashmawy","year":"2013","unstructured":"El-Ashmawy ZK, El-Ashmawy I. Hepato-renal and hematological effects of diclofenac sodium in rats. Glob J Pharmacol. 2013;7:123\u201332.","journal-title":"Glob J Pharmacol"}],"container-title":["Drug Delivery and Translational Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-018-00614-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s13346-018-00614-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-018-00614-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,3,21]],"date-time":"2020-03-21T00:28:12Z","timestamp":1584750492000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s13346-018-00614-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,22]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["614"],"URL":"https:\/\/doi.org\/10.1007\/s13346-018-00614-x","relation":{},"ISSN":["2190-393X","2190-3948"],"issn-type":[{"value":"2190-393X","type":"print"},{"value":"2190-3948","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,22]]},"assertion":[{"value":"22 March 2019","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All institutional and national guidelines for the care and use of laboratory animals were followed. The experiments comply with the current laws of the country in which they were performed. All animal experiments were carried out after obtaining ethical approval from the Institutional Animal Ethical Committee of Amrita Institute of Medical Sciences & Research Centre, Kochi, India.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}