Excipients and Absorption Service

Service Cell Line Transporter Technology Membrane Type Probe Substrate Read Out Reference Inhibitor Positive Control Dynamic Range

Description

SOLVO Biotechnology offers Excipients and Absorption Services for studying the effect of excipients on the bidirectional transport activity of MDR1 and BCRP and on passive permeability using Caco-2 monolayers.

The assay is validated for permeation enhancers that work through transient opening of the tight junctions as well as for excipients that block MDR1 and BCRP transporters. Blockade of these transporters is a subtle and specific strategy to enhance absorption.

SOLVO’s Excipients and Absorption Service contains a set of assays:

1) Solubility Determination
2) Cytotoxicity Measurement
3) Passive Permeability Study: tests the effect of excipients on the transport of reference passive permeability controls on Caco-2 cells
4) MDR1 Interaction Study: determines the effect of excipients on the bidirectional transport of an MDR1 substrate (digoxin) in Caco-2 cells
5) BCRP Interaction Study: determines the effect of excipients on the bidirectional transport of a BCRP substrate (estrone-3-sulfate) in Caco-2 cells

Scientific background

Intestinal absorption enhancement has always been a critical issue in drug development. Current estimates put the number of BCS/BDDCS Class II drugs at 70% of all candidates in the pipeline (1). BCS/BDDCS Class II drugs are high permeability, low solubility compounds where absorption could be limited by efflux transporters, such as MDR1 and BCRP in apical membrane of enterocytes (2).

Absorption enhancement by excipients could be achieved by different methods including the following:

1) Inhibition of the MDR1 and BCRP transporters by excipients leads to greater permeability of drugs (3, 4, 5, 6, 7). The widely used intestinal absorption model, Caco-2 expresses most transporters present in small intestinal epithelial cells including MDR1 and BCRP, and thus is capable of predicting effects on absorption conferred by drug-transporter interactions (8).

2) Another method is transient opening of the tight junctions between enterocytes. Excipients classified as permeation enhancers often work through this less specific method (9). Permeation enhancement can also be studied in Caco-2 cells (9).

Thus, excipients are versatile tools (10). Wise selection will yield higher fraction absorbed (Fa) values. Excipients are tools to improve formulation used by companies developing generics and supergenerics. It is also a tool for life cycle management.

References:

1. Hauss, D. J., Ed. (2007). New York, Informa Healthcare.
2. Shugarts, S. and Benet, L. Z. (2009) Pharm Res. 26: 2039-2054.
3. Shono, Y. et al. (2004) J Pharm Sci. 93: 877-885.
4. Yamagata, T. et al. (2007) Drug Metab Dispos. 35: 1142-1148.
5. Yamagata, T. et al. (2007) J Control Release. 124: 1-5.
6. Werle, M. (2008) Pharm Res. 25: 500-511.
7. Wang, Q. et al. (2008) Int J Pharm. 356: 12-18.
8. Balimane, P. V. et al. (2006) AAPS J. 8: E1-13.
9. Hayashi, M. and Tomita, M. (2007) Drug Metab Pharmacokinet. 22: 67-77.
10. Aungst, B. J. (2012) AAPS J. 14: 10-18.