A modern view of excipient effects on bioequivalence: case study of sorbitol.
OBJECTIVE
To examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs.


METHODS
Two single-dose, replicated, crossover studies were first conducted in healthy volunteers (N=20 each) to compare the effect of 5 Gm of sorbitol and sucrose on bioequivalence of 150 mg ranitidine or 50 mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (N=24) to determine the threshold of sorbitol effect on bioequivalence of 150 mg ranitidine in solution.


RESULTS
Ranitidine Cmax and AUC0-infinity were decreased by approximately 50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC0-infinity. An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC0-infinity, as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25 Gm or greater.


CONCLUSIONS
As exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other 'common' excipients that may have unintended influence on bioavailability/bioequivalence.
Chen
M-L
ML
Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue Building 21, Rm. 3644, Silver Spring, Maryland 20993-0002, USA. meiling.chen@fda.hhs.gov
Straughn
A B
AB
Sadrieh
N
N
Meyer
M
M
Faustino
P J
PJ
Ciavarella
A B
AB
Meibohm
B
B
Yates
C R
CR
Hussain
A S
AS
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000328:Adult; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005079:Excipients; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics; D010592:Pharmaceutic Aids / Q000494:pharmacology*; D019999:Pharmaceutical Solutions; D011899:Ranitidine / Q000493:pharmacokinetics; D013012:Sorbitol / Q000494:pharmacology*; D013395:Sucrose / Q000494:pharmacology; D013810:Therapeutic Equivalency
D000319:Adrenergic beta-Antagonists; D000897:Anti-Ulcer Agents; D005079:Excipients; D010592:Pharmaceutic Aids; D019999:Pharmaceutical Solutions; D013012:Sorbitol; D013395:Sucrose; D011899:Ranitidine; D008790:Metoprolol