Evaluation of Oral Modified-Release Tablets to Support the Approval of Additional Strengths

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ABSTRACT Oral modified-release (MR) drug products with modulated drug release characteristics (e.g., rate, duration, and the site of drug release) have been widely used to achieve desired therapeutic effects, reduced adverse effects and/or improved patient compliance than conventional oral solid dosage forms. More than half of the FDA approved oral MR drug products are extended-release (ER) tablet products with multiple strengths. Until now, appropriate factors to scale the formulation for additional strengths for oral MR tablets have yet to be determined. Moreover, the key variables affecting drug release mechanism and formulation design spaces for different MR technologies have not been fully understood and identified. The main objectives of this project are to: 1) determine the impact of formulation variables (e.g., drug properties and excipients) on the drug release mechanism of in-house made ER tablets based on quality-by-design (QbD) principles; 2) develop mechanistic models parameterized with dissolution data obtained using comprehensive dissolution testing technologies to compare the ER tablets and the corresponding reference drug products across multiple strengths to establish dissolution safe spaces and to identify critical quality attributes (CQA’s); and 3) construct a “proof-of-concept” machine learning model leveraging the database of complex oral MR drug products to identify key variables that affect drug release mechanisms for different formulation design strategies. The proposed research builds upon our extensive research on the formulation development, comparative product characterization, in vitro dissolution testing as well as bioequivalence assessment and mechanistic modeling of complex oral MR solid dosage forms. Biopharmaceutics classification system (BCS) Class I and Class II compounds ropinirole hydrochloride and nifedipine will be studied as model drugs, respectively. ER tablets across multiple strengths with formulation and process variables will be produced and comparatively characterized using the corresponding reference drug products as controls. The drug release mechanism and in vitro dissolution profiles of the ER tablets across multiple strengths will be characterized under different testing conditions including fasted and fed conditions with simulated gastrointestinal motility. Moreover, mechanistic models (e.g., physiologically based pharmacokinetic (PBPK), physiologically based biopharmaceutics models (PBBM)-PBPK) parameterized with the in vitro data obtained will be developed to identify appropriate factors to scale the formulation for additional strengths for oral MR tablets. Lastly, a comprehensive database of the approved oral MR drug products will be established, and ML techniques will be employed to identify the key variables that impact drug release mechanism. The proposed research will help advance the regulatory review and approval processes of oral MR tablet products, and support the approval of additional strengths for such drug products. Facilitating the development of complex generic oral MR drug products will ultimately help increase the public access to high quality and affordable oral medications.