Subchronic Oral Toxicity of Salcaprozate Sodium (SNAC) in Sprague-Dawley and Wistar Rats

Abstract

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.

Intestinal permeation enhancers for oral peptide delivery

“…This carrier had a no observed adverse effect level (NOAEL) of 1 g/kg/day in rats [368], well above the doses used in oral peptide formulations. SNAC was tested in a number of clinical studies especially with heparin in phase III (PROTECT), where an oral liquid dose of heparin-SNAC failed to meet its primary endpoint; moreover compliance in this trial was low due to the bitterness of SNAC in solution, which had previously been noted in proof of principle clinical testing [369].…”

Formulation Strategies to Improve Oral Peptide Delivery

“…Specialised drug delivery companies have selected such excipients where possible, while others have funded studies designed to achieve 'GRAS status' for their delivery agents [267]. This is important because in order to effectively control chronic diseases, the dosage form should be amenable to regular administration.…”

Safety concerns over the use of intestinal permeation enhancers: A mini-review

“…Riley et al, carried out a sub-chronic oral toxicity test of SNAC in rats and found a no observed adverse effect (NOAEL) level of 1 g/kg/day in rats, with a massive dose of 2 g/kg/day eventually causing significant mortality. 26 Gastrointestinal (GI) effects such as emesis and diarrhea were observed in studies involving monkeys at a huge dose of 1.8 g/kg/day. A number of clinical studies have been published involving SNAC and also the related enhancer, 5-CNAC.…”