Research ArticlesEffect of Common Excipients on Caco-2 Transport of Low-Permeability Drugs
Section snippets
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.
REFERENCES (19)
Intestinal permeation enhancers
J Pharm Sci
(2000)- et al.
Epithelial transport of drugs in cell culture. VIII: Effects of sodium dodecyl sulfate on cell membrane and tight junction permeability in human intestinal epithelial (Caco-2) cells
J Pharm Sci
(1993) - et al.
Mechanistic roles of neutral surfactants on concurrent polarized and passive membrane transport of a model peptide in Caco-2 cells
J Pharm Sci
(1997) - et al.
Chitosans as absorption enhancers of poorly absorbable drugs. 3: Influence of mucus on absorption enhancement
Eur J Pharm Sci
(1999) - et al.
Intestinal absorption of octreotide: N-Trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo
J Pharm Sci
(2000) - et al.
Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells
Biochem Biophys Res Commun
(1991) - et al.
Development of a more rapid, reduced serum culture system for Caco-2 monolayers and application to the biopharmaceutics classification system
Int J Pharm
(2000) Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system
(2000)- et al.
A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability
Pharm Res
(1995)