Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat.

Staffan Berg,Frank Seeliger,Denny Suljovic,Bertil Abrahamsson,Christel A S Bergström,Andreas M Hugerth,Nigel Davies,Magnus Söderberg,Natalie Van Zuydam,Marta Perez-Alcazar,Lillevi Kärrberg

doi:10.1021/acs.molpharmaceut.1c00724

Staffan Berg, Frank Seeliger + Show 9 more

Open Access

https://doi.org/10.1021/acs.molpharmaceut.1c00724

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Abstract

In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50–300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60–120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

Highlights

Sodium caprate (C10) is one of the most studied permeation enhancers for improving oral absorption of compounds with low permeability, such as peptide- and nucleotide-based drugs, across the epithelium of the gastrointestinal tract
C10 is the basis of the gastrointestinal permeation enhancement technology I (GIPET I) platform developed by Merrion Pharmaceuticals, typically containing 500 mg of C10 as an enteric-coated tablet, and has been used in numerous clinical studies in GIPET and other formulations.[1−8] In these studies, estimated bioavailability values were single-digit with high variability
The absorption of FITC-dextran 4000 (FD4), the superficial mucosal injury, and the duration of the window for absorption increased with increasing C10 concentrations with substantial FD4 absorption and concomitant erosion of the enterocyte layer observed at the highest studied C10 concentration of 300 mM

Summary

■ INTRODUCTION

Sodium caprate (C10) is one of the most studied permeation enhancers for improving oral absorption of compounds with low permeability, such as peptide- and nucleotide-based drugs, across the epithelium of the gastrointestinal tract. Maher and colleagues observed a 33-fold increase in FD4 AUC compared to controls when FD4 was instilled with 100 mM C10 to the rat jejunum at an administration volume of 0.2 mL/100 g, corresponding to a C10 dose of 7.8−9.7 mg.[40] In the present work, the AUC increase compared to controls was 4.9-fold for administrations with 50 mM C10 (7.8 mg C10 dose), 12.9-fold for 100 mM C10 (16 mg C10), and 26.3-fold for administrations with 300 mM C10 (47 mg C10) Intestinal fluid components, such as bile salts and phospholipids, have been suggested to interact with permeation enhancers, reducing the fraction of the free enhancer available to interact with the intestinal epithelium.[41] To investigate if bile salts and phospholipids can affect the absorption of FD4 when co-delivered with C10, FD4 and C10 were dissolved in buffer alone or in the simulated intestinal fluids FaSSIF-V2 or FeSSIF-V2. Another study using the permeation enhancer SNAC showed lower octreotide apparent permeability in an ex vivo model when formulated in FaSSIF-V2 and rat simulated intestinal fluid, rSIF, compared to when delivered in Krebs−Henseleit buffer.[43]

■ CONCLUSIONS

Findings

■ REFERENCES