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We conducted pharmacokinetic research wherein salcaprozate sodium (SNAC) was utilized as a penetration enhancer by incorporating it into pancreatic kininogenase (PK) to improve the bioavailability of pancreatic kininogenase enteric‐coated tablets. We conducted in vitro studies on PK using the Caco‐2 cell model and quantified PK levels using the enzyme‐linked immunosorbent assay (ELISA) method. We conducted methodological verification by blending SNAC and PK powders into enteric‐coated capsules, and studied the pharmacokinetic characteristics. Based on the PK transport assay, the cumulative permeation rates of the test group that employed a SNAC to PK ratio of 32:1, 16:1, 8:1, 4:1, and 2:1 were 13.574%, 7.597%, 10.653%, 3.755%, and 2.523%, respectively. We conducted a uniformity test on the powder that contained a blend of SNAC and PK. The relative standard deviations (RSDs) for both the power containing SNAC and the power not containing SNAC were less than 10%. Based on the methodological verification, in vivo pharmacokinetic study of PK met the experimental requirements. As indicated by the results of in vivo pharmacokinetic research on rats, the test group (This group used SNAC) had a PK AUC0–12 h of 5679.747 ng/L*h and t1/2 of 4.569 h, while the control group (This group did not use SNAC) had a PK AUC0–12 h of 4639.665 ng/L*h and t1/2 of 3.13 h. This study has established a low‐cost, environmentally friendly, and safe SNAC synthesis route with high process yield suitable for industrial production. SNAC demonstrates an absorption‐enhancing effect on PK, and the optimal ratio of SNAC to PK is determined to be 32:1. [ABSTRACT FROM AUTHOR]

Abstract We conducted pharmacokinetic research wherein salcaprozate sodium (SNAC) was utilized as a penetration enhancer by incorporating it into pancreatic kininogenase (PK) to improve the bioavailability of pancreatic kininogenase enteric‐coated tablets. We conducted in vitro studies on PK using the Caco‐2 cell model and quantified PK levels using the enzyme‐linked immunosorbent assay (ELISA) method. We conducted methodological verification by blending SNAC and PK powders into enteric‐coated capsules, and studied the pharmacokinetic characteristics. Based on the PK transport assay, the cumulative permeation rates of the test group that employed a SNAC to PK ratio of 32:1, 16:1, 8:1, 4:1, and 2:1 were 13.574%, 7.597%, 10.653%, 3.755%, and 2.523%, respectively. We conducted a uniformity test on the powder that contained a blend of SNAC and PK. The relative standard deviations (RSDs) for both the power containing SNAC and the power not containing SNAC were less than 10%. Based on the methodological verification, in vivo pharmacokinetic study of PK met the experimental requirements. As indicated by the results of in vivo pharmacokinetic research on rats, the test group (This group used SNAC) had a PK AUC0–12 h of 5679.747 ng/L*h and t1/2 of 4.569 h, while the control group (This group did not use SNAC) had a PK AUC0–12 h of 4639.665 ng/L*h and t1/2 of 3.13 h. This study has established a low‐cost, environmentally friendly, and safe SNAC synthesis route with high process yield suitable for industrial production. SNAC demonstrates an absorption‐enhancing effect on PK, and the optimal ratio of SNAC to PK is determined to be 32:1.

To date, teduglutide, a peptide analog to the endogenous Glucagon-Like Peptide-2 (GLP-2), represents the most effective pharmacologic treatment to improve the absorption of nutrients in short bowel syndrome (SBS) patients. Currently, this peptide drug cannot be administered orally due to its negligible permeability and rapid degradation in the gastrointestinal tract; and thus, requires patients to take daily sub-cutaneous injections. In SBS patients, oral drug delivery has additional challenges because the site of absorption, the intestine, is short and less functional. Results of the reported herein study in rats, indicate that a novel, SNAC-based oral drug delivery platform designed to enable gastro-mucosal absorption of therapeutic peptides and proteins, may be utilized for the delivery of intestinotrophic peptides in the unique population of SBS patients, as a convenient alternative to daily injections. [ABSTRACT FROM AUTHOR]

Drug delivery systems (DDS) for oral delivery of peptide drugs contain excipients that facilitate and enhance absorption. However, little knowledge exists on how DDS excipients such as permeation enhancers interact with the gastrointestinal mucus barrier. This study aimed to investigate interactions of the permeation enhancer sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) with ex vivo porcine intestinal mucus (PIM), ex vivo porcine gastric mucus (PGM), as well as with in vitro biosimilar mucus (BM) by profiling their physical and barrier properties upon exposure to SNAC. Bulk mucus permeability studies using the peptides cyclosporine A and vancomycin, ovalbumin as a model protein, as well as fluorescein-isothiocyanate dextrans (FDs) of different molecular weights and different surface charges were conducted in parallel to mucus retention force studies using a texture analyzer, rheological studies, cryo-scanning electron microscopy (cryo-SEM), and single particle tracking of fluorescence-labelled nanoparticles to investigate the effects of the SNAC-mucus interaction. The exposure of SNAC to PIM increased the mucus retention force, storage modulus, viscosity, increased nanoparticle confinement within PIM as well as decreased the permeation of cyclosporine A and ovalbumin through PIM. Surprisingly, the viscosity of PGM and the permeation of cyclosporine A and ovalbumin through PGM was unaffected by the presence of SNAC, thus the effect of SNAC depended on the regional site that mucus was collected from. In the absence of SNAC, the permeation of different molecular weight and differently charged FDs through PIM was comparable to that through BM. However, while bulk permeation of neither of the FDs through PIM was affected by SNAC, the presence of SNAC decreased the permeation of FD4 and increased the permeation of FD150 kDa through BM. Additionally, and in contrast to observations in PIM, nanoparticle confinement within BM remained unaffected by the presence of SNAC. In conclusion, the present study showed that SNAC altered the physical and barrier properties of PIM, but not of PGM. The effects of SNAC in PIM were not observed in the BM in vitro model. Altogether, the study highlights the need for further understanding how permeation enhancers influence the mucus barrier and illustrates that the selected mucus model for such studies should be chosen with care. [Display omitted] • SNAC increases viscosity of ex vivo PIM resulting in decreased particle diffusion. • Effects of SNAC are different in ex vivo PGM and PIM. • The BM model shows similar macromolecular permeability as ex vivo PIM. • Utilization of several techniques improves understanding of SNAC-mucus interactions. [ABSTRACT FROM AUTHOR]

Oral delivery of peptides and proteins is hindered by their rapid proteolysis in the gastrointestinal tract and their inability to permeate biological membranes. Various drug delivery approaches are being investigated and implemented to overcome these obstacles. In the discussed study conducted in pigs, an investigation was undertaken to assess the effect of combination of a permeation enhancer – salcaprozate sodium, and a proteolysis inhibitor – soybean trypsin inhibitor, on the systemic exposure of the peptide teriparatide, following intraduodenal administration. Results demonstrate that this combination achieves significantly higher Cmax and AUC (~10- and ~20-fold respectively) compared to each of these methodologies on their own. It was thus concluded that an appropriate combination of different technological approaches may considerably contribute to an efficient oral delivery of biological macromolecules.

Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making.

Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl) amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter and may be a useful means for improving the absorption of certain nutrients and pharmaceutical agents. Presented herein is a subset of data from a larger study evaluating the potential effects of SNAC on the gestation, parturition, lactation, maternal behavior, and offspring development of rats. Pregnant Crl:CD BR VAF/Plus female rats (F0; n = 25) received SNAC at 1000 mg/kg/d orally (gavage) from implantation through lactation and weaning. F1 pups were exposed in utero and potentially through maternal milk; observations continued through sexual maturity. The study concluded with Caesarean sectioning of F1 dams for litter observations and fetal evaluations. No deaths, abortions, premature deliveries, or gross lesions occurred in (F0) dams. Excess salivation, red perivaginal substance, and slight reductions in body weights, body weight gains, and/or feed intake were noted in late gestation/early lactation. SNAC was associated with a prolonged gestation period, leading to a greater number of dams with stillborn pups, higher number of stillborn pups, and reduced live litter size. Offspring body weights/gains, feed consumption, age of sexual maturation, mating, fertility, behavioral parameters, and organ weights at necropsy were unaffected by SNAC. No gross external changes were observed in F1 or F2 pups. In summary, SNAC administered orally at 1000 mg/kg/d to pregnant rats from gestation to weaning resulted in a slight decrease in maternal body weights (-3.8%) and prolonged gestation, along with an increase in stillbirths, but had no effects on growth and development in surviving offspring. [ABSTRACT FROM AUTHOR]

Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl) amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter, and its potential therapeutic applications as a delivery agent for oral forms of heparin and insulin have been explored in a number of clinical investigations. However, limited information about its nonclinical safety is available in the published scientific literature. As part of a larger study exploring the safety of SNAC in combination with heparin, Sprague-Dawley (SD) rats (20/sex/group) received SNAC alone at 2000 mg/kg/d orally (gavage) for 13 weeks (females were terminated after 10 weeks). In a separate study assessing the safety of SNAC in combination with ibandronate, Wistar rats (10/sex/ group) received SNAC alone at levels of 100, 500, or 1000 mg/kg/d orally for 13 weeks. SNAC-related mortality was evident only at the 2000-mg/kg/d level, 20% among males and 50% among females; no clear cause of death was evident. No mortality was seen in the Wistar rat study at doses up to 1000 mg/kg/d. Some differences in clinical pathology parameters, including slightly altered electrolyte levels and lower globulin levels, were seen in SD and Wistar rats. Although these differences reached statistical significance, parameters were within historical control ranges. Liver and kidney weights were slightly higher in SNAC-treated animals of both strains, with no corresponding histopathological changes. These changes may therefore constitute an adaptive response. Histopathological changes were seen in the stomach in both studies, probably secondary to irritation caused by the dosing method. Based on the results of these studies, a no-observed-adverse-effect level (NOAEL) cannot be given for SD rats. The NOAEL for SNAC in Wistar rats was considered to be 1000 mg/kg/d. [ABSTRACT FROM AUTHOR]

Oral delivery of peptides and proteins is hindered by their rapid proteolysis in the gastrointestinal tract and their inability to permeate biological membranes. Various drug delivery approaches are being investigated and implemented to overcome these obstacles. In the discussed study conducted in pigs, an investigation was undertaken to assess the effect of combination of a permeation enhancer - salcaprozate sodium, and a proteolysis inhibitor - soybean trypsin inhibitor, on the systemic exposure of the peptide teriparatide, following intraduodenal administration. Results demonstrate that this combination achieves significantly higher Cmax and AUC (~10- and ~20-fold respectively) compared to each of these methodologies on their own. It was thus concluded that an appropriate combination of different technological approaches may considerably contribute to an efficient oral delivery of biological macromolecules., Competing Interests: None., (© 2021 The Author(s).)

Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making. [ABSTRACT FROM AUTHOR]