Influence of Drug Properties and Formulation on In Vitro Drug Release and Biowaiver Regulation of Oral Extended Release Dosage Forms

Abstract

Abstract. Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory guidance should be reevaluated to assure consistent safety and efficacy among different strengths.KEY WORDS: bioequivalence; biowaiver; extended release; in vitro drug release; in vivo evaluations; proportionally similar strength.

Fenofibrate modified-release pellets with lag phase and high oral bioavailability

“…In fact, it is often challenging to determine whether or how a change in dissolution observed may impact in vivo performance in the absence of an in vitro-in vivo correlation (IVIVC), because the relationship between in vitro behaviors and in vivo performance of modified-release drug products is complex and dependent highly on many variables related to drug substance, product design, formulation, test method, and their interplays. Lin et al also showed four possible scenarios linking in vitro drug release to in vivo performance, including the case that formulations passing F 2 criteria exhibited different in vivo performance 28. In the current study, other dissolution conditions such as different pH and different paddle rotation speed were optimized (data not shown), but establishing IVIVC for the modified-release fenofibrate pellets remains a challenge.…”

Relationship between compression pressure, mechanical strength and release properties of tablets

“…The viscosity of this gel layer and its diffusional path length determine the release rate rather than the compression pressure or tablet hardness. 37,38 These factors (viscosity and diffusional path length of the gel layer) are the rate-determining step in matrix tablet dissolution.…”

Hypoglycemic activities and biochemical parameters modulation of herbal formulations of Allium cepa L. in alloxanized diabetic rats

“…Various formulation factors such as type and concentration of disintegrants, binders, lubricants and hardness or compression force do affect drug release from tablets. A complex relationship exists between in vitro dissolution or performance of a drug and in vivo performance, and this depends on the characteristics of the specific drug molecules, product design and in vitro test conditions (Lin et al, 2016).…”