The biological effects of commonly used excipients

Abstract

Efflux transporters such as ABCB1 (P-gp) and ABCC2 (MRP-2) expressed on the apical membranes of epithelial cells of the intestine represent a formidable barrier for the effective delivery of a plethora of pharmaceutically relevant compounds. Excipients have attracted significant interest in their role as efflux protein inhibitors. To this end, the aim of this study was to examine the biological effects of commonly used excipients, and utilise this information in the design and manufacture of orally disintegrating tablets (ODT) using a design of experiments (DoE) approach. The ‘gold standard’ model of assessing intestinal efflux modulation remains the Caco-2 Transwell® model. As this method is time and resource consuming, a novel high-throughput screening assay was developed to screen excipients for activity against the ABCB1 and ABCC2 transporters using the specific fluorescent probes rhodamine 123 (R-123) and 5(6)-carboxy-2′,7′-dichlorofluorescein (CDF) respectively. Of all the excipients screened, surfactants showed the highest efficacy against ABCB1 with some materials showing lower IC50 values than the established inhibitors verapamil (VER) and ciclosporin (CsA). One of the lead candidate excipients, poloxamer 407, was incorporated into a high-dose (795 mg) and a low-dose (295 mg) paracetamol (acetaminophen, APAP) formulation at 2 % (w/w). Whilst the development of the high-dose tablets was terminated with a disintegration time of 37 s, conforming to European Pharmacopeia specifications, the low-dose tablets were selected for manufacture using a rotary tablet press. These final formulations had disintegration times of 9-43 s over a range of compressions (6-23 kN), providing tablets that conform to both the European Pharmacopeia and United States Pharmacopeia. Taken with a 250 mL glass of water, these tablets are capable of delivering 5.9 mg of poloxamer 407 to give a final concentration of 2.36 x 10 -3 % (w/v), 2.7 times higher than the determined IC50 value for this excipient. To investigate an additional method of incorporating surfactants into ODTs, granules containing ibuprofen were coated in a Kollicoat IR solution containing 2 % (w/v) PEG 2000, poloxamer 407 or Cremophor EL. The ODTs made from these granules by direct compression produced tablets with disintegration times below 30 seconds, showing the viability of this complementary method of propagating the surfactant content of oral dosage formulations.