25A design of experiments (DOE) approach (2-level full factorial design) was used to investigate the effect of several formulation and process variables on the properties of fast disintegrating tablets comprising starch-based pellets and excipient granules and to optimize and validate the design space. The percentage of starch pellets (30-50% w/w), type of disintegrants (Ac-di-sol, Explotab, Polyplasdone), percentage of external disintegrant (4-8% w/w) and 30 compression force (5-15 kN) were the evaluated factors (24 runs + 9 centre points = 33 experiments), while tablet hardness, friability and disintegration time were the studied tablet properties (responses).Starch pellets were prepared by extrusion-spheronisation. Excipient granules containing microcrystalline cellulose, lactose, internal disintegrant (8%) and polyvinylpyrrolidone K-30 35(4%) were prepared by wet granulation. Pellets, granules (700-1000 µm) and external disintegrant were mixed and compressed into oblong tablets (17.1 mm long, 8.2 mm wide).Evaluation of the effects calculated from the DOE results showed that a lower concentration of starch pellets and higher compression force were required to yield tablets with a high hardness, a low friability (<1%) and short disintegration time (<3 min). Polyplasdone granules had the 40 lowest porosity and friability which was reflected in the DOE study, where the Polyplasdonecontaining tablets were harder, less friable and disintegrated faster compared to Ac-di-sol and Explotab-containing tablets. Monte carlo simulations at the optimal factor settings (30% starch pellets, 4% Polyplasdone and 10 kN compression force) indicated that a robust system was formed as the probability to exceed the limits was low for all responses. Validation of the design 45 3 space (at optimal settings) showed that the results predicted via the DOE models correlated well with the observed experimental data. KEYWORDS

27Background: For any new vaginal dosage form, the distribution and retention in the vagina 28 has to be assessed by in-vivo evaluation. We evaluated the vaginal distribution and retention of 29 starch-based pellets in sheep as live animal model by gamma scintigraphy (using Indium-111 30DTPA as radiolabel) and in women via magnetic resonance imaging (MRI, using a gadolinium 31 chelate as contrast agent). A conventional cream formulation was used as reference in both studies.

We have developed fast-disintegrating tablets comprising starch-based pellets and excipient granules for intravaginal drug delivery. The purpose of this study was to evaluate the intravaginal disintegration, distribution and retention behavior of these tablets in sheep and women using colposcopy as visualization technique. One tablet was administered to each study subject (n = 6) and repeated colposcopy examination was performed over a 48 h and 24 h period in sheep and women, respectively. Colposcopy in sheep indicated that in vivo tablet disintegration was initiated within 30 min of vaginal administration and that due to disintegration of the pellets themselves, the formulation was transformed into a gel-like mass which distributed throughout the entire vaginal cavity within 2-4 h. In vivo tablet disintegration after intravaginal administration to women was complete within 4 h, whereby the formulation gradually spread throughout the vaginal cavity as complete covering was observed after 12 and 24 h. The persistent retention (up to 24 and 48 h in women and sheep, respectively) confirmed the long retention time of this vaginal formulation.