Abstract
Labrasol® is a self-emulsifying excipient that contains saturated polyglycolysed C6–C14 glycerides and this additive is known to improve the intestinal absorption of poorly absorbed drugs after oral administration. However, the effects of formulations similar to Labrasol® on the intestinal absorption of poorly absorbed drugs have not been characterized. In this study, we used insulin as a model peptide drug and examined the absorption-enhancing effects of Labrasol® and its related formulations for insulin absorption in rats. The co-administration of Labrasol-related formulations with insulin reduced the blood glucose levels. Among these formulations, Capryol 90 was the most effective additive. Notably, the effect of Capryol 90 was greater at pH 3.0 than at pH 7.0. Additionally, almost no mucosal damage was observed in the presence of these formulations, as these formulations did not affect the activity of lactate dehydrogenase (LDH) and the amount of protein released from the small intestine. In mechanistic studies, Capryol 90 improved the stability of insulin and suppressed the association with insulin under acidic conditions. The loosening of the tight junctions (TJs) could be the underlying mechanism by which Capryol 90 improved intestinal insulin absorption via a paracellular route. These findings suggest that Capryol 90 is an effective absorption enhancer for improving the intestinal absorption of insulin, without inducing serious damage to the intestinal epithelium.
Highlights
As medical technology advances and several therapeutic agents are being developed, the demand for easy-to-administer and non-invasive formulations increases
Following the intestinal administration of insulin alone, almost no effect was observed on the pPlahasrmmaaceugtilcus 2c0o2s0,e12l,exvels, with significant hypoglycemic effects observed following the 6inofte19stinal administration of Labrasol®, Capryol 90, and Lauroglycol 90 in the insulin solution when compared with itnhteesctionnaltraodlmgirnoisutpra.tioTnabolfeL2absruasmolm®,aCraizperysotlh9e0,pahnadrmLaaucroodglyyncoalm9i0cinpathraeminesutelirns sfoollulotiwoninwgheinnsulin admicnoimstpraatrieodnwwitihththeeaccohntarbolsogrroputipo.nTaebnlhe a2nscuemrmtoartihzeesstmheapllhianrtmesatciondaylnlaomopicspoafrarmatest.erAs sfoilnlodwicinagted in insulin administration with each absorption enhancer to the small intestinal loops of rats
The present study demonstrates that Labrasol® and its related formulations can enhance the intestinal insulin absorption from the intestine
Summary
As medical technology advances and several therapeutic agents are being developed, the demand for easy-to-administer and non-invasive formulations increases. Various strategies have been studied to improve the intestinal absorption of peptide and protein drugs. Among these strategies, the use of formulation additives, including absorption enhancers and protease inhibitors, remains a promising approach [2,3,4,5,6,7]. We have assessed the intestinal absorption of carboxyfluorescein (CF) and FITC-dextran 4000 (FD4), and 10% (v/v) Labrasol® increases the bioavailability of these compounds [16]. To mediate this action of Labrasol®, C8 and C10 moieties are important components, as well as PEG esters and glycerides [17]. The absorption-enhancing effects of Labrasol-related formulations need to be comprehensively elucidated
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