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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.

Injectable PAMAM Dendrimer–PEG Hydrogels for the Treatment of Genital Infections: Formulation and in Vitro and in Vivo Evaluation