title: Injectable PAMAM dendrimer-PEG hydrogels for the treatment of genital infections: formulation and in vitro and in vivo evaluation.
abstract: Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, an in situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine) [G4-(NH(2))(64)] dendrimer with peripheral thiopyridyl terminations is cross-linked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in vivo in a pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in vivo studies in guinea pig showed that 100-200 μL of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in the maternal tissues without crossing the fetal membranes into the fetus. The dendrimer gels were stable up to 72 h, and the in vivo biodegradation of gel occurred after 72 h; this correlated well with the in vitro degradation pattern. The pH of the vagina was not altered upon application of the gel, and none of the animals aborted up to 72 h after application of gel. The histological evaluation of the cervical tissues showed absence of edema in the epithelial cell layer, no sloughing of the epithelial or superficial mucous layer, and absence of necrosis and infiltration of inflammatory cells in the submucosal layers, confirming that tissues were tolerant to the gel. The immunohistofluorescence images showed the localization of the gel components on the superficial mucified epithelial layer. The cross-linking density and swelling of hydrogels was impacted by the polymer content, and the 10% hydrogels exhibited the highest cross-link density. The in vitro drug release studies carried out using Franz diffusion cells showed that amoxicillin release from 6 and 10% gels was sustained for 240 h as compared to 3% gels. As the polymer concentration increased to 10%, the release pattern from gels approached diffusion controlled mechanism with diffusional exponent n = 0.49. In conclusion, the biodegradable in situ forming hydrogels of the present study offer a therapeutic option to provide sustained localized delivery of amoxicillin intracervically to the pregnant woman for the treatment of ascending genital infections.
authors: Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA.
authors: Raghavendra S
authors: RS
authors: Navath
authors: Anupa R
authors: AR
authors: Menjoge
authors: Hui
authors: H
authors: Dai
authors: Roberto
authors: R
authors: Romero
authors: Sujatha
authors: S
authors: Kannan
authors: Rangaramanujam M
authors: RM
authors: Kannan
references: Nat Rev Drug Discov. 2002 Dec;1(12):977-85
references: 12461519
references: Drug Discov Today. 2010 Mar;15(5-6):171-85
references: 20116448
references: Antimicrob Agents Chemother. 2003 Dec;47(12):3784-8
references: 14638483
references: J Nutr. 2003 May;133(5 Suppl 2):1668S-1673S
references: 12730483
references: Biomacromolecules. 2008 Oct;9(10):2863-72
references: 18800810
references: J Control Release. 2001 Dec 13;77(3):323-32
references: 11733099
references: Contraception. 1998 Oct;58(4):245-9
references: 9866007
references: Biol Reprod. 2005 Aug;73(2):308-14
references: 15829622
references: Biomacromolecules. 2010 Jun 14;11(6):1544-63
references: 20415504
references: Biomacromolecules. 2007 Jan;8(1):240-51
references: 17206813
references: J Control Release. 1998 Dec 4;56(1-3):75-83
references: 9801431
references: Nanomedicine (Lond). 2010 Nov;5(9):1317-29
references: 21128716
references: Bioconjug Chem. 2008 Dec;19(12):2446-55
references: 19053299
references: AAPS PharmSciTech. 2006 Apr 14;7(2):E38
references: 16796356
references: Antimicrob Agents Chemother. 2000 Sep;44(9):2471-4
references: 10952597
references: Int J Pharm. 2006 Aug 2;318(1-2):1-14
references: 16621366
references: J Pharm Sci. 2010 Aug;99(8):3514-21
references: 20222027
references: AAPS PharmSciTech. 2005 Oct 24;6(3):E504-12
references: 16354011
references: Eur J Med Chem. 2007 Jul;42(7):1032-8
references: 17336426
references: J Pharm Sci. 1999 Jun;88(6):592-8
references: 10350494
references: Am J Obstet Gynecol. 2004 Oct;191(4):1205-11
references: 15507942
references: Macromol Biosci. 2004 Jun 25;4(6):575-8
references: 15468250
references: Bioconjug Chem. 2008 Aug;19(8):1660-72
references: 18610944
references: Drug Dev Ind Pharm. 2009 May;35(5):515-24
references: 19040181
references: J Control Release. 2010 Mar 19;142(3):447-56
references: 19896998
references: Biomacromolecules. 2006 Jan;7(1):310-6
references: 16398530
references: AAPS PharmSciTech. 2008;9(2):505-20
references: 18431651
references: Antimicrob Agents Chemother. 2006 May;50(5):1696-700
references: 16641437
references: Contraception. 2009 Apr;79(4):297-303
references: 19272499
references: Macromol Biosci. 2004 Feb 20;4(2):71-5
references: 15468196
references: Pharm Res. 1991 Nov;8(11):1401-7
references: 1798677
references: Biol Reprod. 1998 Aug;59(2):431-6
references: 9687318
references: Biomaterials. 2009 Apr;30(11):2112-21
references: 19171376
references: Int J Pharm. 2007 Oct 1;343(1-2):106-21
references: 17587518
references: Biomaterials. 2010 Jun;31(18):5007-21
references: 20346497
references: Biomacromolecules. 2007 Jun;8(6):1807-11
references: 17511499
references: Mol Biosyst. 2009 Oct;5(10):1148-56
references: 19756304
references: Biomacromolecules. 2010 Mar 8;11(3):666-73
references: 20108892
references: Int J Pharm. 2010 Aug 16;395(1-2):298-308
references: 20580797
references: Biomaterials. 2009 Mar;30(8):1453-61
references: 19097642
references: Int J Gynaecol Obstet. 1995 Apr;49(1):1-7
references: 9457977
references: Antimicrob Agents Chemother. 2004 Nov;48(11):4342-8
references: 15504863
references: Adv Drug Deliv Rev. 2005 Dec 14;57(15):2215-37
references: 16297497
references: J Mater Sci Mater Med. 2008 Nov;19(11):3365-71
references: 18545941
references: Drug Dev Ind Pharm. 2001 Jul;27(6):541-7
references: 11548861
references: Best Pract Res Clin Obstet Gynaecol. 2007 Jun;21(3):391-402
references: 17512255
references: Int J Pharm. 2002 Jul 8;241(1):155-63
references: 12086731
references: AAPS PharmSciTech. 2003;4(1):E7
references: 12916916
references: Arch Gynecol Obstet. 1990;247(1):1-13
references: 2178562
references: Int J Pharm. 2006 Apr 7;312(1-2):66-74
references: 16464549