Impact of osmotically active excipients on bioavailability and bioequivalence of BCS class III drugs.

The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has been widely used to predict drug absorption during pharmaceutical development (1). Recently, the system has also been employed in regulatory practice to determine if waiver of in vivo bioavailability or bioequivalence studies (i.e., biowaivers) can be granted for an immediate-release solid oral dosage form (2). In this regard, the US Food and Drug Administration (FDA) currently allows biowaivers for BCS class I (highly soluble and highly permeable) drugs formulated in immediate release, rapidly dissolving drug products (2). Since the publication of the FDA Guidance on BCS in 2000, however, there has been continued interest in the possible extension of BCS-based biowaivers, particularly for class III drugs that exhibit high solubility and low permeability (3–5). One of the major challenges to the allowance of biowaivers for BCS class III drugs is related to the potential effects of excipients on drug absorption (6). Historically, excipients were considered inert substances that could be used mainly in the manufacture of drug products as diluents, fillers, binders, lubricants, coatings, solvents, and dyes (7). However, with the advances in pharmaceutical science, some “active” excipients have been found to be capable of influencing drug absorption or bioavailability through a variety of mechanisms, such as modification in solubility/dissolution, change in intestinal permeability (including transporters), and modulation of gastrointestinal (GI) motility (8–20). To further investigate the effects of “active” excipients on the absorption of BCS class III drugs, this paper examines those that may modulate GI motility and affect the transit time of drugs in the gut. In a recent FDA contract study, sorbitol was shown to decrease ranitidine absorption, which was attributed to an increased GI fluid volume from the osmotic load of sorbitol, resulting in enhanced GI motility and reduced ranitidine transit time in the small intestine, a primary absorption site for the drug (19). Similarly, mannitol (an isomer of sorbitol) was reported to decrease the bioavailability of cimetidine in solution or as chewable tablets (10). Both ranitidine and cimetidine are BCS class III drugs that exhibit site-dependent absorption characteristics (19). Polyethylene glycol (PEG) 400, a commonly used excipient for enhancing drug solubility, was also found to accelerate small intestine transit and adversely influence the absorption of ranitidine (15,16,20). It is noted that all of these excipients (sorbitol, mannitol, and PEG 400) are osmotically active at the amounts relevant to those used in pharmaceutical formulations (21). From a regulatory perspective, to extend BCS-based biowaivers or allow biowaivers for minor changes in manufacturing and/or formulation, it is essential to know the threshold level of an “active” excipient incorporated in the formulation that would influence the bioavailability of the drug and/or change the outcome of bioequivalence. In the case of osmotically “active” excipients, sorbitol has been shown to decrease the bioavailability of ranitidine in a linear dose–response manner (19). However, the influence of PEG 400 on ranitidine absorption was reported to be concentration dependent (16). The aims of this article were to (a) review the dose–response relationship of various osmotically active excipients on drug absorption, (b) determine the threshold levels of these excipients in affecting bioavailability or bioequivalence, and (c) discuss the regulatory implications of using these excipients in the formulation with a poorly permeable drug.