Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations.

Background: Modified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug's rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers' understanding regarding the biopharmaceutics properties that supported approval of these products' ER claims, as per 21 CFR 320.25(f), and DR claims.

Methods: A comprehensive search was conducted using the FDA's internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping.

Results: Out of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results-most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label.

Conclusion: The results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA's assessment of ER claims.