Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals

Kim, Jae Cheon; Park, Eun Ji; Na, Dong Hee

doi:10.3390/ph15121585

Cited by 13 publications

(6 citation statements)

References 150 publications

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“…It should also be noted that the 5 days preterm and 5 days near-term received different infant formulas, which may have contributed to the characteristics of mucus. Furthermore, although C10 is approved as a food additive 56 , used in infant formula 17 , and tested at the gram scale without any reported genotoxicity or subchronic toxicity 57 , this compound is also known to increase transmucosal permeation of macromolecules when used within a two- to three-digit mM range in rodents in vivo 58 , 59 . Nevertheless, further work is needed to understand how C10 interacts with mucus and explore any opportunities to improve conditions with impaired mucus barrier.…”

Section: Discussionmentioning

confidence: 99%

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation

Mortensen,

Bohr,

Krog

et al. 2024

Sci Rep

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The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

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Section: Discussionmentioning

confidence: 99%

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation

Mortensen,

Bohr,

Krog

et al. 2024

Sci Rep

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“…Similarly, EDTA 2Na is known to increase the paracellular transport of hydrophilic compounds in a concentration-dependent manner in Caco-2 cells in vitro and in rats in situ and in vivo. It was also reported that, after the application of high EDTA concentrations of more than 6 mM (2.02 mg/mL) for 45 min, the transepithelial electrical resistance (TEER) did not recover to the TEER value before EDTA treatment, but, at the lower concentrations of EDTA such as 2 and 3 mM (1.01 mg/mL), the TEER recovered again while the permeability of sodium fluorescein remained at an elevated level in Caco-2 cells [ 46 , 48 , 49 , 50 ]. In in vivo conditions, the decreased TEER recovers to the TEER value before EDTA treatment due to the re-distribution of cationic metals from blood circulation, and the elevated permeability was rapidly decreased to the level in the absence of EDTA 2Na.…”

Section: Discussionmentioning

confidence: 99%

Development and Evaluation of EDTA-Treated Rabbits for Bioavailability Study of Chelating Drugs Using Levofloxacin, Ciprofloxacin, Hemiacetal Ester Prodrugs, and Tetracycline

et al. 2023

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Laboratory rabbits are fed foods rich with cationic metals, and while fasting cannot empty gastric contents because of their coprophagic habits. This implies that, in rabbits, the oral bioavailability of chelating drugs could be modulated by the slow gastric emptying rates and the interaction (chelation, adsorption) with gastric metals. In the present study, we tried to develop a rabbit model with low amounts of cationic metals in the stomach for preclinical oral bioavailability studies of chelating drugs. The elimination of gastric metals was achieved by preventing food intake and coprophagy and administering a low concentration of EDTA 2Na solution one day before experiments. Control rabbits were fasted but coprophagy was not prevented. The efficacy of rabbits treated with EDTA 2Na was evaluated by comparing the gastric contents, gastric metal contents and gastric pH between EDTA-treated and control rabbits. The treatment with more than 10 mL of 1 mg/mL EDTA 2Na solution decreased the amounts of gastric contents, cationic metals and gastric pH, without causing mucosal damage. The absolute oral bioavailabilities (mean values) of levofloxacin (LFX), ciprofloxacin (CFX) and tetracycline hydrochloride (TC), chelating antibiotics, were significantly higher in EDTA-treated rabbits than those in control rabbits as follows: 119.0 vs. 87.2%, 9.37 vs. 13.7%, and 4.90 vs. 2.59%, respectively. The oral bioavailabilities of these drugs were significantly decreased when Al(OH)3 was administered concomitantly in both control and EDTA-treated rabbits. In contrast, the absolute oral bioavailabilities of ethoxycarbonyl 1-ethyl hemiacetal ester (EHE) prodrugs of LFX and CFX (LFX-EHE, CFX-EHE), which are non-chelating prodrugs at least in in vitro condition, were comparable between control and EDTA-treated rabbits irrespective of the presence of Al(OH)3, although some variation was observed among rabbits. The oral bioavailabilities of LFX and CFX from their EHE prodrugs were comparable with LFX and CFX alone, respectively, even in the presence of Al(OH)3. In conclusion, LFX, CFX and TC exhibited higher oral bioavailabilities in EDTA-treated rabbits than in control rabbits, indicating that the oral bioavailabilities of these chelating drugs are reduced in untreated rabbits. In conclusion, EDTA-treated rabbits were found to exhibit low gastric contents including metals and low gastric pH, without causing mucosal damage. Ester prodrug of CFX was effective in preventing chelate formation with Al(OH)3 in vitro and in vivo, as well as in the case of ester prodrugs of LFX. EDTA-treated rabbits are expected to provide great advantages in preclinical oral bioavailability studies of various drugs and dosage formulations. However, a marked interspecies difference was still observed in the oral bioavailability of CFX and TC between EDTA-treated rabbits and humans, possibly due to the contribution of adsorptive interaction in rabbits. Further study is necessary to seek out the usefulness of the EDTA-treated rabbit with less gastric contents and metals as an experimental animal.

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“…To commemorate this new era of bioavailable peptide drugs, this review article summarizes the technological progress in improving the oral absorption of new drug modalities and discusses future prospects to improve absorption enhancement. Since numerous review articles about oral absorption enhancement technology have already been published [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], this manuscript provides a brief explanation of these technologies in Section 2 . However, the main focus of this manuscript involves shedding light on new aspects of orally bioavailable middle-to-large molecules, mainly based on information in the recent (from 2020 to 2023) literature available in PubMed, in order to keep readers up to date with the latest technology.…”

Section: Introductionmentioning

confidence: 99%

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Asano,

Takakusa,

Nakai

2023

Pharmaceutics

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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.

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Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals

Cited by 13 publications

References 150 publications

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation

Development and Evaluation of EDTA-Treated Rabbits for Bioavailability Study of Chelating Drugs Using Levofloxacin, Ciprofloxacin, Hemiacetal Ester Prodrugs, and Tetracycline

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

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