Vaginal distribution and retention of tablets comprising starch-based multiparticulates: evaluation by colposcopy.

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.

Effect of disintegrants on the properties of multiparticulate tablets comprising starch pellets and excipient granules.

A 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 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 (4%) were prepared by wet granulation. Pellets, granules (700-1000 µm) and external disintegrant were mixed and compressed into oblong tablets (17.1mm long, 8.2mm 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 lowest porosity and friability which was reflected in the DOE study, where the Polyplasdone-containing 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 space (at optimal settings) showed that the results predicted via the DOE models correlated well with the observed experimental data.

Vaginal distribution and retention of a multiparticulate drug delivery system, assessed by gamma scintigraphy and magnetic resonance imaging.

BACKGROUND: For any new vaginal dosage form, the distribution and retention in the vagina has to be assessed by in vivo evaluation. We evaluated the vaginal distribution and retention of starch-based pellets in sheep as live animal model by gamma scintigraphy (using Indium-111 DTPA as radiolabel) and in women via magnetic resonance imaging (MRI, using a gadolinium chelate as contrast agent). A conventional cream formulation was used as reference in both studies. METHOD: Cream and pellets were administered to sheep (n=6) in a two period-two treatment study and to healthy female volunteers (n=6) via a randomized crossover trial. Pellets (filled into hard gelatin capsule) and cetomacrogol cream, both labeled with Indium-111 DTPA (for gamma scintigraphy) or with gadolinium chelate (for MRI) were evaluated for their intravaginal distribution and retention over a 24h period. Spreading in the vagina was assessed based on the part of the vagina covered with formulation (expressed in relation to the total vaginal length). Vaginal retention of the formulation was quantified based on the radioactivity remaining in the vaginal area (sheep study), or qualitatively evaluated (women study). RESULTS: Both trials indicated a rapid distribution of the cream within the vagina as complete coverage of the vaginal mucosa was seen 1h after dose administration. Clearance of the cream was rapid: about 10% activity remained in the vaginal area of the sheep 12h post-administration, while after 8h only a thin layer of cream was detected on the vaginal mucosa of women. After disintegration of the hard gelatin capsule, the pellet formulation gradually distributed over the entire vaginal mucosa. Residence time of the pellets in the vagina was longer compared to the semi-solid formulation: after 24h 23 ± 7% radioactivity was detected in the vaginal area of the sheep, while in women the pellet formulation was still detected throughout the vagina. CONCLUSION: A multi-particulate system containing starch-based pellets was identified as a promising novel vaginal drug delivery system, resulting in complete coverage of the vaginal mucosa and long retention time.