Title:A Systematic Evaluation of Solubility Enhancing Excipients to Enable the Generation of Permeability Data for Poorly Soluble Compounds in Caco-2 Model
Volume: 8
Issue: 2
Author(s): Devang Shah, Sundeep Paruchury, Muralikrishna Matta, Gajendra Chowan, Murali Subramanian, Ajay Saxena, Matthew G. Soars, John Herbst, Roy Haskell, Punit Marathe and Sandhya Mandlekar
Affiliation:
Keywords:
BCRP, Caco-2, co-solvents, excipients, permeability, P-gp, poor recovery, poor solubility, transporters.
Abstract: The study presented here identified and utilized a panel of solubility enhancing excipients to enable the
generation of flux data in the Human colon carcinoma (Caco-2) system for compounds with poor solubility. Solubility
enhancing excipients Dimethyl acetamide (DMA) 1 % v/v, polyethylene glycol (PEG) 400 1% v/v, povidone 1% w/v,
poloxamer 188 2.5% w/v and bovine serum albumin (BSA) 4% w/v did not compromise Caco-2 monolayer integrity as
assessed by trans-epithelial resistance measurement (TEER) and Lucifer yellow (LY) permeation. Further, these
excipients did not affect P-glycoprotein (P-gp) mediated bidirectional transport of digoxin, permeabilities of high
(propranolol) or low permeability (atenolol) compounds, and were found to be inert to Breast cancer resistant protein
(BCRP) mediated transport of cladribine. This approach was validated further using poorly soluble tool compounds,
atazanavir (poloxamer 188 2.5% w/v) and cyclosporine A (BSA 4% w/v) and also applied to new chemical entity (NCE)
BMS-A in BSA 4% w/v, for which Caco-2 data could not be generated using the traditional methodology due to poor
solubility (<1 µM) in conventional Hanks balanced salt solution (HBSS). Poloxamer 188 2.5% w/v increased solubility of
atazanavir by >8 fold whereas BSA 4% w/v increased the solubility of cyclosporine A and BMS-A by >2-4 fold thereby
enabling permeability as well as efflux liability estimation in the Caco-2 model with reasonable recovery values. To
conclude, addition of excipients such as poloxamer 188 2.5% w/v and BSA 4% w/v to HBSS leads to a significant
improvement in the solubility of the poorly soluble compounds resulting in enhanced recoveries without modulating
transporter-mediated efflux, expanding the applicability of Caco-2 assays to poorly soluble compounds.
