Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system.
The objectives were 1) to design a continuous dissolution/Caco-2 system to predict the dissolution-absorption relationships for fast and slow dissolving formulations of piroxicam, metoprolol tartrate, and ranitidine HCl, and compare the predicted relationships with observed relationships from clinical studies; 2) to estimate the effect of croscarmellose sodium on ranitidine dissolution-absorption relationships; and 3) to estimate the effect of solubilizing agents on piroxicam dissolution-absorption relationships. A continuous dissolution/Caco-2 system was constructed from a dissolution apparatus and a diffusion cell, such that drug dissolution and permeation across a Caco-2 monolayer would occur sequentially and simultaneously. The continuous system generally matched observed dissolution-absorption relationships from clinical studies. For example, the system successfully predicted the slow metoprolol and slow ranitidiine formulations to be permeation-rate-limited. The system predicted the slow piroxicam formulation to be dissolution-rate-limited, and the fast piroxicam formulation to be permeation-rate-limited, in spite of piroxicam's high permeability and low solubility. Additionally, the system indicated croscarmellose sodium enhanced ranitidine permeability and predicted solubilizing agents to not modulate permeability. These results suggest a dissolution/Caco-2 system to be an experimentally based tool that may predict dissolution-absorption relationships from oral solid dosage forms, and hence the relative contributions of dissolution and permeation to oral drug absorption kinetics.
Ginski
M J
MJ
School of Pharmacy, University of Maryland, 20 North Pine Street, Baltimore, MD 21201, USA.
Taneja
R
R
Polli
J E
JE
D000042:Absorption; D018938:Caco-2 Cells; D002266:Carboxymethylcellulose Sodium / Q000494:pharmacology; D002463:Cell Membrane Permeability; D006801:Humans; D008790:Metoprolol / Q000378:metabolism / Q000493:pharmacokinetics*; D010894:Piroxicam / Q000378:metabolism / Q000493:pharmacokinetics*; D011899:Ranitidine / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility
D010894:Piroxicam; D011899:Ranitidine; D008790:Metoprolol; D002266:Carboxymethylcellulose Sodium