title: Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation.
abstract: In this work, poloxamer (PL)-based binary hydrogels, composed of PL 407 and PL 188, were studied with regard to the physicochemical aspects of sol-gel transition and pharmaceutical formulation issues such as dissolution-release profiles. In particular, we evaluated the cytotoxicity, genotoxicity, and in vivo pharmacological performance of PL 407 and PL 407-PL 188 hydrogels containing tramadol (TR) to analyze its potential treatment of acute pain. Drug-micelle interaction studies showed the formation of PL 407-PL 188 binary systems and the drug partitioning into the micelles. Characterization of the sol-gel transition phase showed an increase on enthalpy variation values that were induced by the presence of TR hydrochloride within the PL 407 or PL 407-PL 188 systems. Hydrogel dissolution occurred rapidly, with approximately 30%-45% of the gel dissolved, reaching ~80%-90% up to 24 hours. For in vitro release assays, formulations followed the diffusion Higuchi model and lower K(rel) values were observed for PL 407 (20%, K(rel) = 112.9 ± 10.6 μg · h(-1/2)) and its binary systems PL 407-PL 188 (25%-5% and 25%-10%, K(rel) =80.8 ± 6.1 and 103.4 ± 8.3 μg · h(-1/2), respectively) in relation to TR solution (K(rel) =417.9 ± 47.5 μg · h(-1/2), P<0.001). In addition, the reduced cytotoxicity (V79 fibroblasts and hepatocytes) and genotoxicity (V79 fibroblasts), as well as the prolonged analgesic effects (>72 hours) pointed to PL-based hydrogels as a potential treatment, by subcutaneous injection, for acute pain.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, São Paulo, Brazil.
authors.forename: Ana Claudia Mendonça
authors.initials: AC
authors.lastname: dos Santos
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, São Paulo, Brazil.
authors.forename: Alessandra Cristina Santos
authors.initials: AC
authors.lastname: Akkari
authors.affiliation: Faculdades Integradas Metropolitanas de Campinas, Campinas, São Paulo, Brazil.
authors.forename: Iasmin Rosanne Silva
authors.initials: IR
authors.lastname: Ferreira
authors.affiliation: Departamento de Biotecnologia, Universidade de Sorocaba, Sorocaba, São Paulo, Brazil.
authors.forename: Cintia Rodrigues
authors.initials: CR
authors.lastname: Maruyama
authors.affiliation: Departamento de Biotecnologia, Universidade de Sorocaba, Sorocaba, São Paulo, Brazil.
authors.forename: Monica
authors.initials: M
authors.lastname: Pascoli
authors.affiliation: Departamento de Bioquímica, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors.forename: Viviane Aparecida
authors.initials: VA
authors.lastname: Guilherme
authors.affiliation: Departamento de Bioquímica, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors.forename: Eneida
authors.initials: E
authors.lastname: de Paula
authors.affiliation: Departamento de Engenharia Ambiental, Universidade Estadual 'Júlio de Mesquita Filho', Sorocaba, São Paulo, Brazil.
authors.forename: Leonardo Fernandes
authors.initials: LF
authors.lastname: Fraceto
authors.affiliation: Departamento de Biotecnologia, Universidade de Sorocaba, Sorocaba, São Paulo, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: de Lima
authors.affiliation: Faculdades Integradas Metropolitanas de Campinas, Campinas, São Paulo, Brazil.
authors.forename: Patrícia da Silva
authors.initials: Pda S
authors.lastname: Melo
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, São Paulo, Brazil.
authors.forename: Daniele Ribeiro
authors.initials: DR
authors.lastname: de Araujo
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D020100:Hydrogels / Q000737:chemistry / Q000633:toxicity; D007700:Kinetics; D008823:Micelles; D044367:Phase Transition; D020442:Poloxamer / Q000737:chemistry / Q000633:toxicity; D014147:Tramadol / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D020100:Hydrogels; D008823:Micelles; D020442:Poloxamer; D014147:Tramadol
keywords: analgesia; cytotoxicity; genotoxicity; micelle
references.citation: Int J Clin Pharmacol Ther. 2010 Feb;48(2):138-45
references.pmid: 20137766
references.citation: ScientificWorldJournal. 2012;2012:564939
references.pmid: 22778699
references.citation: BMC Anesthesiol. 2014;14:33
references.pmid: 24914400
references.citation: Eur J Pharm Biopharm. 2008 Jan;68(1):34-45
references.pmid: 17881200
references.citation: Drug Dev Ind Pharm. 2012 Apr;38(4):468-83
references.pmid: 21942308
references.citation: J Control Release. 1998 Mar 2;52(1-2):169-78
references.pmid: 9685947
references.citation: Int J Pharm. 2009 Jul 6;376(1-2):176-85
references.pmid: 19409463
references.citation: Brain Res. 2008 May 19;1210:76-83
references.pmid: 18417104
references.citation: J Colloid Interface Sci. 2008 Dec 15;328(2):278-87
references.pmid: 18845304
references.citation: Int J Pharm. 2005 Aug 26;300(1-2):22-31
references.pmid: 15967608
references.citation: Pain Pract. 2009 Jan-Feb;9(1):71-81
references.pmid: 19019047
references.citation: Br J Clin Pharmacol. 1996 Jan;41(1):7-12
references.pmid: 8824687
references.citation: Langmuir. 2007 Aug 28;23(18):9229-36
references.pmid: 17676776
references.citation: Drug Dev Ind Pharm. 2010 Aug;36(8):885-92
references.pmid: 20184418
references.citation: J Control Release. 2010 May 10;143(3):290-301
references.pmid: 20074598
references.citation: J Pharm Sci. 2013 Aug;102(8):2707-17
references.pmid: 23839931
references.citation: J Immunol Methods. 1986 May 22;89(2):271-7
references.pmid: 3486233
references.citation: Acta Anaesthesiol Scand. 2003 Sep;47(8):1006-12
references.pmid: 12904194
references.citation: Eur J Pharm Sci. 2002 Nov;17(3):161-7
references.pmid: 12393144
references.citation: Exp Cell Res. 1988 Mar;175(1):184-91
references.pmid: 3345800
references.citation: Langmuir. 2005 Jul 5;21(14):6170-8
references.pmid: 15982018
references.citation: Int J Pharm. 2003 Sep 16;263(1-2):105-11
references.pmid: 12954185
references.citation: Adv Biomed Res. 2013 Jul 30;2:68
references.pmid: 24223383
references.citation: Int J Pharm. 2005 Jan 20;288(2):235-44
references.pmid: 15620863
references.citation: Acta Pharm. 2009 Mar;59(1):15-30
references.pmid: 19304555
references.citation: J Control Release. 2002 Aug 21;82(2-3):189-212
references.pmid: 12175737
references.citation: J Biomed Mater Res A. 2010 Jan;92(1):378-85
references.pmid: 19191317
references.citation: Eur J Clin Pharmacol. 2009 Apr;65(4):343-53
references.pmid: 19252905
references.citation: J Colloid Interface Sci. 2009 Jan 1;329(1):54-61
references.pmid: 18930467
references.citation: Int J Nanomedicine. 2011;6:151-66
references.pmid: 21499415
references.citation: Pharm Res. 1995 Dec;12(12):1997-2002
references.pmid: 8786979
references.citation: J Colloid Interface Sci. 2005 May 1;285(1):74-9
references.pmid: 15797398
references.citation: Int J Pharm. 2006 Dec 11;327(1-2):81-8
references.pmid: 16949225
references.citation: Pharm Res. 2003 Oct;20(10):1581-90
references.pmid: 14620511
references.citation: J Biomed Mater Res. 1972 Nov;6(6):571-82
references.pmid: 4642986
references.citation: Langmuir. 2010 Jul 6;26(13):10561-71
references.pmid: 20465298
references.citation: Int J Pharm. 2000 Apr 10;199(1):85-93
references.pmid: 10794930
references.citation: Colloids Surf B Biointerfaces. 2008 Jun 1;63(2):229-35
references.pmid: 18249098
references.citation: Ther Clin Risk Manag. 2007 Oct;3(5):819-29
references.pmid: 18473006
references.citation: Toxicol In Vitro. 2000 Aug;14(4):345-9
references.pmid: 10906441
references.citation: Chem Soc Rev. 2008 Aug;37(8):1473-81
references.pmid: 18648673
references.citation: Acta Anaesthesiol Scand. 2009 Oct;53(9):1207-13
references.pmid: 19659681
references.citation: Pharm Res. 2006 Dec;23(12):2709-28
references.pmid: 17096184
references.citation: J Biomed Mater Res A. 2004 Sep 1;70(3):459-66
references.pmid: 15293320