(W1030-04-20) Evaluation of In Vitro Performance Attributes of Imvexxy® (Estradiol) Vaginal Insert

Purpose: Imvexxy^® (estradiol) vaginal inserts are small, light pink, tear-shaped inserts for manual placement into the vagina. The insert contains two components: a “shell” that encapsules a “fill” formulation. In order to understand the effect of formulation and manufacturing process parameters on the quality and performance of such vaginal inserts, it is necessary to develop appropriate in vitro performance test methods that are sensitive and discriminating. This study aimed to develop such test methods and evaluate the critical performance attributes of vaginal inserts using Imvexxy^® (estradiol) vaginal insert as a model drug product.

Methods: The disintegration time of the shell of the insert was assessed at several agitation rates and using different volumes of simulated vaginal fluid (SVF). The disintegration time was recorded as the first appearance of the fill formulation in the SVF. Additionally, the distribution of estradiol between an oil phase and an external aqueous media (SVF) over 4 hours was studied at two “high” and “low” concentrations (Fig. 1). The diffusion rate of estradiol across the oil-aqueous interface between the two phases was determined from the slope of the concentration in receiver phase (oil phase or SVF) vs. time profile. The release of estradiol from the insert emulsified in SVF and the extracted fill formulation emulsified in SVF at various stirring rates was evaluated using Franz diffusion cells. Additionally, in order to evaluate the impact of the emulsification on drug release, estradiol release from emulsified and non-emulsified fill formulation and inserts in presence and absence of disintegrated gelatin “shells” was also evaluated by the reverse dialysis method using Float-A-Lyzer cells. The sensitivity of the reverse dialysis method to globule size of the emulsified fill formulation was evaluated after emulsifying the fill formulation using the M110P microfluidizer at various homogenization pressures to produce nanoemulsions of small, medium, and large globules.

Results: Disintegration of the shell occurred at the seam line with the disintegration time (ranging from 2 to 60 minutes) was found to be inversely proportional to the agitation rate applied to the SVF. At both the high and low loading concentrations of estradiol, the diffusion rate of estradiol from aqueous SVF to the oil phase was greater than the diffusion rate of estradiol from the oil phase to the aqueous SVF. Therefore, it is hypothesized that estradiol will be spatially located within the emulsified oil droplets as the fill formulation is released and mixed with the vaginal secretions. Additionally, a greater diffusion rate of estradiol from SVF to the oil phase was observed at the high loading concentration compared to the low loading concentration. Using the Franz diffusion cells, an increase in the release of estradiol from the emulsified fill formulation and emulsified insert was observed as the stirring rate was increased (Fig. 2). The release of estradiol from the non-emulsified and emulsified fill formulation decreased in the presence of the disintegrated gelatin shell in the external media using the reverse dialysis method. The release rates of estradiol from the fill formulation emulsified to small, medium, and large globule sizes were similar using the reverse dialysis method.

Conclusion: This study revealed that the disintegration properties of the gelatin “shell” and the distribution and equilibration of drug among the two phases of the emulsified fill formulation may be critical performance characteristics of these vaginal inserts. Further studies are underway to investigate the effects of the critical material attributes and the microstructural properties of the emulsified formulations on the performance characteristics.


Figure 1: Study design to evaluate the diffusion rate of estradiol between an oil phase and an aqueous phase (SVF) over 4 hours. (A) Diffusion of estradiol from the oil phase to the aqueous phase (Do/w) at low loading concentration (37 µg estradiol/1 mL of oil) and high loading concentration (185 µg estradiol/1 mL of oil). (B) Diffusion of estradiol from the aqueous phase to the oil phase (Dw/o) at low loading concentration (3.7 µg estradiol/1 mL of SVF) and high loading concentration (18.5 µg estradiol/1 mL of SVF).


Figure 2: (A) Cumulative amount of estradiol released versus time (B) Cumulative amount of estradiol released versus square root of time (C) Cumulative percentage of estradiol released versus square root of time at various stirring rates from either emulsified fill formulation (top row) or emulsified insert (bottom row) using Franz diffusion cells (n=3 replicates; mean ± SD).