Development of muds for improved vaginal therapy

Abstract

Bacterial vaginosis is a common cause of vaginitis, condition often treated with oral metronidazole. However, due to unpleasant side effects, patient compliance is often reduced. Vaginal tablet with bioadhesive properties could enable a prolonged residence time and a sustained release of a drug at the site of infection. Vagina as a drug administration site is attractive due to high surface area, rich blood supply and avoidance of first pass metabolism. The aim of the study was development and characterisation of bioadhesive multiparticulate delivery system (MUDS) for vaginal delivery of metronidazole. Metronidazole was mixed with chitosan of different degrees of deacetylation (DD) and/or pectin of different degrees of methoxylation (DM). The drug content was kept constant at 10 % (w/w) throughout the experiments. A 22 – factorial design with centre point for was used to screen for the combination of 50:50 ratios of chitosan type (DD 77%, 82% and 92%) and pectin type (DM 10%, 25% and 40%) with high bioadhesion to cow vaginal tissue. The max detachment force (Fmax) and work of adhesion (AUC) were determined using 11 mm flat faced tablets and vaginal tissue by Texture Analyser (Stable Microsystem, UK). Chitosan DD 92 % was selected as the chitosan type for further optimization studies since this was found to have the largest influence on the bioadhesion of 11 mm tablets to vaginal tissue. For further optimization studies, different ratios of pectin (DM 10% and 40%) and chitosan (DD 92%) were mixed with the drug (10%, w/w), and concave mini-tablets (2 mm) were produced by direct compression (compression force 241.49 ± 10.22 MPa) using 15–tip multiple tooling. Tensile strength, friability and simulated wetting time of the mini-tablets were tested. Dissolution rate of mini–tablets was determined using the paddle method (100 rpm and 37 ْC) in vaginal fluid stimulant (VFS) pH 4.5 and 6.8. A modified version of rotating cylinder method was applied for bioadhesive studies of mini–tablets using cow rectal tissue to determine the percentage remaining mini-tablets on the tissue after rotating at 250 rpm for 10 minutes. The combination of 70 % chitosan DD 92 % and pectin DM 40% showed the strongest bioadhesive properties as well as the slowest release of metronidazole from the mini–tablets in VFS. The highest degree of cross–linking was seen in media of high pH (pH 6.8) and for higher amount of esterification in the molecule. All formulations showed low friability and tensile strength between 12-25 N/mm2, except those containing only pectin. To conclude, it is possible to obtain desired mucoadhesive strength and sustained release of metronidazole in mini–tablets by combining chitosan of high deacetylating degree with pectin type of low methoxylation degree. The tablets show sufficient tensile strength and friability.