Abstract
Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.
Highlights
Oral administration is the preferred route of treatment for low molecular mass drugs for their ease of intake and high patient compliance [1]
This rat single-pass intestinal perfusion (SPIP) study is part of a sequence of mechanistic studies evaluating the in vivo effect of permeation-enhancing (PE) excipients on intestinal transport of model drugs and marker compounds during various luminal conditions [11,12,13,14]
We investigated the direct effects of two permeation enhancers (PE) on the intestinal lumen-to-blood effective permeability (Peff) of two peptide drugs, enalaprilat and hexarelin, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr-EDTA)
Summary
Oral administration is the preferred route of treatment for low molecular mass drugs for their ease of intake and high patient compliance [1]. A thoroughly investigated strategy for oral peptide delivery is to reduce the integrity of the intestinal membrane barrier This approach may be achieved with permeation enhancers (PE), called absorption-modifying excipients, incorporated into the oral drug formulation [4]. As long as there are no concerns with luminal stability, a PE may increase the permeation of a peptide drug dissolved in the intestinal lumen [5]. This approach was recently FDA approved for semaglutide, a modified peptide containing 31 amino acids. Semaglutide has favorable properties for oral delivery: Pdhiasrsmoalcveuetdicsin20t2h0,e12in, 9t9estinal lumen [5] This approach was recently FDA approved for semagluti2doef,1a3 modified peptide containing 31 amino acids. Tohf epsreesctluindiycaolbmjecotdiveelss.wTehreeseevasltuuadteydobbyjeacptipvleysinwg ethree einvasliutuatSePdIbPymaopdpelyl iinngrtahte, winhsiicthu iSsPcIoPnmsioddeerel dinarnati,nwvhivicohrieslecovnansitdmeroeddealntoininvviveostrigelaetveatnhtemeffodecetl otof vinavrieosutisgaatgeetnhtes oefnfedcitreocftvianrtieosutisnaagl eenptitshoenliadlirtreacnt sinptoerstt.inal epithelial transport
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