(W1030-06-35) Impact of Material Attributes on In Vitro Performance of Clindamycin Phosphate Vaginal Creams

Purpose: Unlike topical drug products applied to the skin, characterization-based bioequivalence (BE) approaches that can mitigate the risks associated with potential failure modes for BE have yet to be established for locally acting vaginal drug products. Differences in material attributes of inactive ingredients (such as differences in grade, sources, etc.) have the potential to influence the physicochemical and structural attributes of vaginal creams, which may impact product performance. Therefore, it is essential to investigate and understand the influence of material attributes on the critical quality attributes (CQA) and in vitro release and permeation of the active ingredient(s) from vaginal creams to support characterization-based BE approaches. The objective of this study was to investigate the impact of variations in an inactive ingredient (cetostearyl alcohol (CSA)) on the CQAs and in vitro performance of clindamycin phosphate (CP) vaginal creams.

Methods: Laboratory-made (LM) CP vaginal creams (2% w/w) were prepared with CSA containing different ratios of cetyl alcohol (CA) and stearyl alcohol (SA) (LM-CSA50 vs. LM-CSA70) and compared to a marketed reference listed drug (RLD) CP vaginal cream. The drug content and rheological properties of the CP creams were determined using high performance liquid chromatography (HPLC) and a rheometer, respectively. The droplet size of the CP creams was characterized using an optical microscope; the data was analyzed using ImageJ. The performance of the CP creams was evaluated via an in vitro drug release test (IVRT) and in vitro permeation test (IVPT). The studies were conducted using vertical diffusion cell (VDC) methods with polyethersulfone (PES) (0.45 μm, contact area: 1.77 cm²) and excised porcine vaginal tissue (contact area: 0.2 cm²) for the IVRT and IVPT studies, respectively. Simulated vaginal fluid (pH 4.2) containing 3% (w/v) Brij^®O20 was used as the receptor solution for both IVRT and IVPT studies. The IVRT and IVPT studies were conducted at 37°C (measured at the surface of the membrane or tissue) for 6h and 12h, respectively. The animal tissue integrity and thickness were monitored before and after the 12h IVPT study. Tissues from three animals were utilized for the IVPT study (n=3 cells per formulation per animal). The in vitro release rate (from the IVRT study, n≥6 cells per formulation) and the cumulative amount permeated and maximum permeation flux (J_max) for CP (from the IVPT study) were utilized to compare the products.

Results: The LM CP cream formulations had similar drug content as the RLD cream and a slightly larger droplet size (d50: 4.0-4.2 µm) than the RLD (d50: 3.2 µm). The LM CP creams containing different ratios of CA and SA (i.e., LM-CSA50 and LM-CSA70) are shown below (Figure 1). The in vitro release rates of CP from LM-CSA50 and LM-CSA70 analyzed using the Higuchi model were similar to one another and greater than the release rate of CP from the RLD cream. The preliminary IVPT results suggests that the inactive ingredients in the vaginal creams may influence the permeation of CP through excised vaginal tissue.

Conclusion: An understanding of the impact of material attributes on the physicochemical and structural attributes of the dosage form and thereby its influence on product performance of CP vaginal creams can facilitate the development of characterization-based BE approach for such products. The present research suggests that differences in material attributes of the inactive ingredients may have the potential to influence the physicochemical and structural properties (such as rheology) of vaginal creams. Additional analysis would be necessary to understand the impact of such differences on the performance of vaginal cream drug products.

Acknowledgments: 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 (U01FD006721) totaling $500,000 with 100 percent funded by FDA/HHS. The views 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.

Figure 1. Viscosity vs. shear rate flow curves of LM-CSA50, LM-CSA70, and an RLD product