In Vitro Based Approaches to Evaluate the Bioequivalence of Locally-Acting Rectal and Vaginal Semi-Solid Drug Products

ABSTRACT Locally-acting rectal and vaginal semi-solid products have been widely used for the treatment of diseases and disorders in the rectum and vagina (and/or cervix) over the past few decades. Despite their prevalence, the development and approval of generic versions of these drug products have remained difficult due to the complexity of these products as well as the challenges of conducting bioequivalence (BE) studies with clinical pharmacodynamic (or pharmacokinetic) endpoints. The main objectives of the project are to: 1) identify critical quality attributes (CQA’s) of a variety of semi-solid dosage forms (such as suppositories with/without a gelatin coating and creams) that are common for rectal and vaginal administration; 2) develop in vitro performance test methods and method validation strategies that are unique for these rectal and vaginal products; and 3) elucidate drug permeation mechanisms across the rectal and vaginal mucosal membranes. The proposed research builds upon our previous research on the comparative product characterization and method development and validation of in vitro performance tests (such as in vitro release test (IVRT) and in vitro permeation test (IVPT)) for rectal suppositories and vaginal creams. Miconazole nitrate that is commercially available in a variety of vaginal dosage forms (i.e., suppository with/without a gelatin coating, cream) and mesalamine will be used as the model drugs. Comprehensive characterization of relevant physicochemical and structural properties of a variety of semi-solid dosage forms prevalent for rectal and vaginal administration will be conducted. The quality-by-design (QbD) principles will be implemented to identify CQA’s as well as the key material and processing parameters that can affect the CQA’s and in vitro product performance for a variety of topical rectal and vaginal semi-solid dosage forms. In vitro permeation behavior of a variety of topical semi-solid dosage forms and drugs (e.g., hydrophilic vs. hydrophobic) will be investigated using both animal and human tissues to elucidate drug permeation mechanisms across the mucosal membranes. Lastly, a pilot study on expanding physiologically based pharmacokinetic (PBPK) modeling to support BE assessment of locally-acting rectal and vaginal drug products will be conducted. It is expected that a comprehensive understanding of the CQA’s and their relationship to material and processing differences will be provided for a variety of topical semi-solid dosage forms. Moreover, robust and sensitive in vitro performance test methods and method validation strategies that are unique for rectal and vaginal products will be developed. The proposed research will support the establishment of in vitro comparative product characterization-based BE approaches that are suitable for locally-acting rectal and vaginal semi-solid drug products, thus facilitating the development of generic versions of these drug products and helping advance the regulatory review and approval processes for both innovator and generic drug products. This will ultimately increase the public access to high quality and affordable topical rectal and vaginal medication.