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A regulatory framework to provide regulatory relief based on the in vitro characterization of the drug substance and drug product, termed Biopharmaceutics Classification System (BCS), allows the waiving of clinical BE studies for some immediate-release (IR) solid oral dosage formulations. In vivo bioequivalence (BE) studies are generally needed to demonstrate a lack of impact of significant formulation changes on a drug’s bioavailability during its development, for post-approval manufacturing changes, and when developing generic products. Given the potential excipient risks to drug absorption, changes to drug formulations should consider excipient amount, mechanism(s) in which excipient may impact absorption, and the drug’s absorption properties ( 10, 11). However, other potential concerns such as excipient impact on drug membrane permeability have much less evidence of an effect in vivo ( 5, 6, 7, 8, 9). Osmotically active excipients such as sugar-alcohols (e.g., mannitol, sorbitol) and polyethylene glycol (PEG) 400 are known to potentially reduce drug absorption by increasing GI fluid volume, which in turn dilutes intraluminal drug concentration and reduces small intestinal transit time ( 5). For example, excipients may potentially modify GI transit time and luminal volumes, alter permeability, or modify metabolism within the GI tract ( 4). However, there are several anticipated mechanisms through which excipients in the GI tract could impact drug absorption. It is well appreciated that excipients can alter drug release rate and/or extent of release from dosage formulations. Generally, excipients can potentially have an impact on drug absorption by altering the dosage formulation’s disintegration, dissolution, or stability, or by directly impacting GI physiological processes. Excipients are typically used in dosage formulations to ensure manufacturability and content uniformity but are also used to modulate drug substance or active drug ingredient (API) stability and bioavailability. Non-drug components of the dosage formulation, i.e., excipients, may also impact absorption of the drug. Physiological factors such as gastrointestinal pH, gastric emptying, small intestinal transit time, bile salts, and mechanisms of membrane permeability also influence oral drug absorption ( 3). Important physiochemical properties of the drug include its solubility, intrinsic dissolution rate, ionization (pK a), lipophilicity (log P), stability, surface area, crystallinity, polymorphism, salt form, and molecular size. Oral drug absorption is a process that is influenced by key biopharmaceutical and physiological factors. Of the fraction of the oral dose that is absorbed from the intestinal lumen, the fraction that becomes available in systemic circulation (i.e., is bioavailable) is further reduced by metabolism through the gut wall into the hepatic portal circulation, metabolism by first pass elimination through the liver, and biliary excretion ( 2). Based on the drug’s physiochemical properties, intestinal permeation occurs by passive diffusion or active/facilitative transport ( 1). These biowaivers and excipient risks are discussed here.įollowing oral administration, solid dosage formulations must first disintegrate in the gastrointestinal (GI) tract and dissolve in solution for drug absorption to occur.
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In particular, sugar alcohols have been identified as potential absorption-modifying excipients. Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit.