(T1030-09-48) Understanding Critical Quality Attributes of Gelatin Coated Miconazole Nitrate Vaginal Inserts and Suppositories

Purpose: Presently, the bioequivalence (BE) of a locally-acting generic vaginal insert or suppository to its brand name drug is typically established using a comparative clinical endpoint BE study. The development of in vitro characterization-based BE approaches for vaginal inserts and suppositories may enhance patient access to generic for these vaginal dosage forms. Two common types of locally-acting inserts/suppositories are those composed of a drug-containing hard fat base and those wherein a gelatin coating encapsulates the drug and inactive ingredients. To support the development of characterization-based BE approaches for such products, an understanding of the microstructure of the different insert and suppository types and the impact of the microstructure on drug release is necessary. The present work aims to investigate the critical quality attributes (CQA) of uncoated and gelatin-coated vaginal inserts and suppositories to facilitate the development of a characterization-based BE approach for such drug products.

Methods: Monistat 3® miconazole nitrate (MN) vaginal insert, 200 mg, which includes a “core” encapsulated by a gelatin shell, was chosen as the gelatin-coated insert (“MN insert”). Monistat 3® MN vaginal suppository, 200 mg, which is an uncoated suppository, was chosen as the uncoated control (“MN suppository”). Comparative characterization of the MN insert and MN suppository was carried out to delineate the quality attributes of the gelatin coated formulation, including gas chromatograph-mass spectrometry (GC-MS) to analyze the hydrocarbon composition of the MN insert core and MN suppository; differential scanning calorimetry (DSC) to understand the thermal behavior of the MN insert core and MN suppository; a rheometer to determine viscosity profiles and melting range; and 3-D X-ray microscope (XRM) to characterize the inner structure of MN insert core and MN suppository and the gelatin coat thickness of the MN insert. Moreover, MN particle size was imaged using polarized light microscopy (PLM) and particle size distribution (PSD) was analyzed using ImageJ. Disintegration time (DT) of the MN insert and MN suppository was determined using an automatic disintegration tester at 37°C. Surface dissolution imaging (SDi2) was deployed to understand the impact of the gelatin coating on drug dissolution from the MN insert and MN suppository.

Results: The gelatin coat thickness of the MN insert observed using 3D XRM was 559 ±143.8 μm (n=3) (Figure 1). The DSC thermograms showed multiple crystalline peaks during heating (n=3), possibly due to multiple fatty acid components in the MN insert core and MN suppository, which was consistent with the GC-MS results. Both MN insert core and MN suppository formulations showed Newtonian behavior with a similar viscosity at 37°C (389 ± 20 cP and 391 ± 22 cP, respectively, n=3) and melting range (33.1± 0.77 – 44.0 ± 0.62°C and 33.2 ± 0.42 – 44.1 ± 0.37, respectively, n=3). The MN particle size was comparable (i.e., D50 ~ 2.5 μm, n=1) between the MN insert core and the MN suppository. DT of the MN insert was 7.25 ± 0.36 min (n=6) as
compared to 3.45 ± 0.33 (n=6) for the MN suppository formulation and the increased DT duration was attributed to the presence of the gelatin shell for the insert product. Moreover, the gelatin coat dissolved quickly in contact with the simulated vaginal fluid (SVF) and fully dissolved within 40 minutes at 37°C as visualized using SDi2 during a 24-hour study (n=1) (Figure 2).

Conclusion: The present study delineated the key quality attributes of the gelatin coated MN insert. The MN insert core showed similar physicochemical and rheological properties to the MN suppository. The gelatin coating of the MN insert does not appear to impede MN release significantly when visualized using a flow through method via SDi2. Further studies are being conducted to evaluate the in vitro drug release from the MN insert and MN suppositories using an in vitro release test (IVRT) study. Additionally, studies to prepare and characterize laboratory-made MN inserts with a comparable hydrocarbon composition to the MN insert core are ongoing. Finally, future studies will evaluate the impact of material attribute differences (e.g., gelatin grade) on in vitro MN release from insert formulations.

Acknowledgements: This project is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a grant (1U01FD007656) totaling $500,000 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

3D X-ray microscope images of MN insert showing the gelatin coat thickness.

Representative SDi2 images of MN insert (Monistat 3 insert) and MN suppository (Monistat 3 suppository) during a 24-hour dissolution study in the simulated vaginal fluid (SVF) at 37°C (open-loop, 20 mL/ min for 1 hour followed by closed-loop, 5 mL/min for 23 hours).