Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Persistence of antimicrobial activity through sustained release of triclosan from pegylated silicone elastomers.

Microbial adhesion to silicone elastomer biomaterials is a major problem often resulting in infection and medical device failure. Several strategies have been employed to modulate eukaryotic cell adhesion and to hamper bacterial adherence to polymeric biomaterials. Chemical modification of the surface by grafting of polyethylene glycol (PEG) chains or the incorporation of non-antibiotic antimicrobial agents such as triclosan into the biomaterial matrix may reduce bacterial adhesion. Here, such strategies are simultaneously applied to the preparation of both condensation-cure and addition-cure silicone elastomer systems, seeking a sustained release antimicrobial device biomaterial. The influence of triclosan incorporation and degree of pegylation on antimicrobial release, surface microbial adherence and persistence (Escherichia coli and Staphylococcus epidermidis) were evaluated in vitro. Non-pegylated silicone elastomers provided an increased percentage release of triclosan extending over a relatively short duration (99% release by day 64) compared with their pegylated (4% w/w) counterparts (65% and 72% release by day 64, for condensation and addition-cure systems respectively). Viable E. coli adherence to a non-pegylated silicone elastomer containing 1% w/w triclosan was reduced by over 99% after 24 h compared to the non-pegylated silicone elastomer containing no triclosan. No viable S. epidermidis adhered to any of the triclosan-loaded (>0.1% w/w) formulations other than the control. Persistence of the antimicrobial activity of the triclosan-loaded pegylated silicone elastomers continued for at least 70 days compared to the triclosan-loaded non-pegylated elastomers (at least 49 days). Understanding how PEG affects the release of triclosan from silicone elastomers may prove useful in the development of a biomaterial providing prolonged, effective antimicrobial activity.