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Doxorubicin is a potent chemotherapy drug, but its oral bioavailability is limited due to its low membrane permeability. Thus, absorption enhancers such as zonula occludens toxin and its six-mer fragment, FCIGRL, have been studied to address this issue. This study aimed to evaluate the effectiveness of four peptides (Pep1, Pep2, Pep3, and Pep4) derived from FCIGRL and investigate the changes in the absorption of doxorubicin, to propose an absorption enhancer for doxorubicin. Pep1 is a modified version of FCIGRL in which the hydroxyl group at the C-terminus is replaced with an amino group. Pep2 is a modified Pep1 in which cysteine is replaced with N3-substituted dipropionic acid. Pep3 and Pep4 are Pep2-modified homodimers. Pharmacokinetic analysis was performed in rats after the intraduodenal administration of doxorubicin solutions containing each FCIGRL-modified peptide and the stabilizer levan or benzalkonium chloride (BC). The results showed that Pep3 and Pep4 administered with levan each significantly increased the intestinal absorption of doxorubicin, as did Pep2 administered with levan/BC. In particular, 10 mg·kg−1 of Pep4 with levan significantly increased the area under the curve (AUC)0–240min of doxorubicin by 2.38-fold (p < 0.01) and the peak concentration (Cmax) by 3.30-fold (p < 0.01) compared to the control solution. The study findings indicate that Pep2, Pep3, and primarily Pep4 are novel absorption enhancers that can open tight junctions for doxorubicin, and the effectiveness of the peptides was directly affected by the presence of levan or levan/BC. [ABSTRACT FROM AUTHOR]

To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus® tablets and Mycapssa® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption. [ABSTRACT FROM AUTHOR]

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.

Generally, the use of absorption enhancers might be the most effective approaches to ameliorate the enteric absorption of poorly absorbed substances. Among numerous absorption enhancers, we already reported that a gemini surfactant, sodium dilauramidoglutamide lysine (SLG-30) with two hydrophobic and two hydrophilic moieties, is a novel and promising adjuvant with a high potency in improving the absorption safely. Here, we examined and elucidated the absorption-improving mechanisms of SLG-30 in the enteric absorption of substances. SLG-30 increased the intestinal absorption of 5(6)-carboxyfluorescein (CF) to a greater level than the typical absorption enhancers, including sodium glycocholate and sodium laurate, as evaluated by an in situ closed-loop method. Furthermore, SLG-30 significantly lowered the fluorescence anisotropy of dansyl chloride (DNS-Cl), suggesting that it might increase the fluidity of protein sections in the intestinal cell membranes. Moreover, SLG-30 significantly lowered the transepithelial-electrical resistance (TEER) values of Caco-2 cells, suggesting that it might open the tight junctions (TJs) between the enteric epithelial cells. Additionally, the levels of claudin-1 and claudin-4 expression decreased in the presence of SLG-30. These outcomes propose that SLG-30 might improve the enteric transport of poorly absorbed substances through both transcellular and paracellular routes.

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood⁻brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects.

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. [ABSTRACT FROM AUTHOR]

Generally, the use of absorption enhancers might be the most effective approaches to ameliorate the enteric absorption of poorly absorbed substances. Among numerous absorption enhancers, we already reported that a gemini surfactant, sodium dilauramidoglutamide lysine (SLG-30) with two hydrophobic and two hydrophilic moieties, is a novel and promising adjuvant with a high potency in improving the absorption safely. Here, we examined and elucidated the absorption-improving mechanisms of SLG-30 in the enteric absorption of substances. SLG-30 increased the intestinal absorption of 5(6)-carboxyfluorescein (CF) to a greater level than the typical absorption enhancers, including sodium glycocholate and sodium laurate, as evaluated by an in situ closed-loop method. Furthermore, SLG-30 significantly lowered the fluorescence anisotropy of dansyl chloride (DNS-Cl), suggesting that it might increase the fluidity of protein sections in the intestinal cell membranes. Moreover, SLG-30 significantly lowered the transepithelial-electrical resistance (TEER) values of Caco-2 cells, suggesting that it might open the tight junctions (TJs) between the enteric epithelial cells. Additionally, the levels of claudin-1 and claudin-4 expression decreased in the presence of SLG-30. These outcomes propose that SLG-30 might improve the enteric transport of poorly absorbed substances through both transcellular and paracellular routes. [ABSTRACT FROM AUTHOR]

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood–brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects. [ABSTRACT FROM AUTHOR]