The influence of AT1002 on the nasal absorption of molecular weight markers and therapeutic agents when co-administered with bioadhesive polymers and an AT1002 antagonist, AT1001

Abstract

These findings will assist in understanding the permeation-enhancing capability of and the receptor binding of AT1002. Further, combining AT1002 with carrageenan supports the development of the mucosal delivery of therapeutic agents that have low bioavailability even with bioadhesive agents.

Recent progress in tight junction modulation for improving bioavailability

“…However, this effect was dependent on the coadministration of the bioadhesive polymer carrageenan, which leads to longer membrane contact, allowing longer times for receptor binding of AT1002 and longer absorption times [15,19]. This synergistic effect between bioadhesive polymers and AT1002 in intranasal application was confirmed for saquinavir and salmon calcitonin [86]. Apart from intranasal …”

“…Numerous in vivo studies underlining the potential of AT1002 as a TJ modulator for different administration routes have been reported (Table 2) [69,[84][85][86][95][96][97]. The intestinal absorption of cyclosporine A was significantly increased by coadministration with AT1002 in Sprague-Dawley rats [69].…”

“…Recent studies with the zonulin antagonist AT1001 [87] proved that the zonulin receptor is the target structure of AT1002 [86]. The zonulin receptor was the postulated target for Zot due to its structural similarity to zonulin [86] and was formerly confirmed to be equivalent to PAR-2 [73]. The PARs belong to a unique class of G-protein--coupled receptors that are usually activated by cleavage of their N-terminus by certain serine proteases [88].…”

“…The mechanism of action of AT1002 was investigated in detail by different groups [82,85,86]. Recent studies with the zonulin antagonist AT1001 [87] proved that the zonulin receptor is the target structure of AT1002 [86].…”

“…Intranasal administration [86] PN-159 Galantamine, salmon calcitonin, parathyroid hormone 1 --34 (PTH 1 --34 ), peptide YY3 --36 (PYY 3 --36 ), MC-4RA EpiAirwayÔ * Intranasal administration [100,102,103] Human peptide YY 3 --36 (PYY 3 --36 ) Rabbit Intranasal administration [102] Insulin Human Clinical Phase II; intranasal administration [104,105] Peptide YY 3 --36 (PYY 3 --36 ) Human Clinical Phase II; intranasal administration application, AT1002 was also shown to be valuable as an intratracheal (salmon calcitonin) [85] and a transdermal permeation enhancer [96]. In combination with the Tat protein, the epidermal permeation of small interfering RNA was significantly increased, which could provide a new therapeutic option in the dermal treatment of skin diseases (e.g., atopic dermatitis) [96].…”