Research Articles
Effect of Common Excipients on Caco-2 Transport of Low-Permeability Drugs

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ABSTRACT

The Biopharmaceutics Classification System (BCS) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. The objective of this work was to evaluate the effect of nine individual excipients on the Caco-2 permeability of seven low-permeable compounds that differ in their physiochemical properties. Generally, most excipients had no influence on drug permeability. With the exception of sodium lauryl sulfate, no excipient affected Caco-2 monolayer integrity. Sodium lauryl sulfate moderately increased the permeability of almost all the drugs. Tween 80 significantly increased the apical-to-basolateral direction permeability of furosemide, cimetidine, and hydrochlorothiazide, presumably by inhibiting their active efflux, without affecting mannitol permeability. Additionally, docusate sodium moderately increased cimetidine permeability. Other excipients did not have significant effect on the permeability of these three drugs. Further work is needed to interpret the in vivo consequences of these observations from cell culture. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1776–1786, 2001

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INTRODUCTION

The Biopharmaceutics Classification System (BCS) is an approach to justify a waiver for in vivo bioequivalence.1 BCS-based biowaivers assume the primary reason for bioinequivalence of two immediate-release (IR) products containing same drug is differences in dissolution.2 To justify a BCS-based biowaiver, the drug needs to be a class I drug (highly soluble and highly permeable) and the drug product needs to be rapidly dissolving (i.e., ≥ 85 % dissolution in 30 min). Additionally, the excipients

Materials

[14C]Mannitol (specific activity of 51 mCi/mmol) was obtained from DuPont NEN (Boston, MA). [3H]Acyclovir (specific activity 51.5 Ci/mmol) was purchased from Moravek Biochemicals (Brea, CA). Atenolol, cimetidine, furosemide, and hydrochlorothiazide were purchased from Sigma Chemical Company (St. Louis, MO). Ranitidine hydrochloride was obtained from Spectrum Quality Products (New Brunswick, NJ). All drugs were of USP grade. All organic solvents were of HPLC grade. All other chemicals were

RESULTS

The AP–BL permeabilities of mannitol are listed in Table 2. The AP–BL permeabilities of atenolol, ranitidine hydrochloride, and acyclovir in the absence and presence of individual excipients are listed in Table 3. The AP–BL and BL–AP permeabilities and the ratios of BL–AP permeability versus AP–BL permeability (i.e., B/A ratios) of furosemide and cimetidine, are summarized in Tables 4 and 5, respectively. The AP–BL permeabilities of hydrochlorothiazide in the absence and presence of excipients

Excipient Effects on Pooled Mannitol Permeability

Prior to an examination of individual excipient effects on drugs, the general effect of excipients on mannitol permeability is discussed. Mannitol permeability was simultaneously measured in all samples, providing an opportunity to weigh any potential excipient effect against the general integrity of the monolayer. Average mannitol permeability for control monolayers was 0.688 (± 0.026) × 10−6 cm/s. Mannitol permeability < 1 × 10−6 cm/s was necessary for control monolayers to be acceptable.

For

ACKNOWLEDGEMENTS

This work was supported in part by the Food and Drug Administration.

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