The impact of AT1002 on the delivery of ritonavir in the presence of bioadhesive polymer, carrageenan

Abstract

New insights into the modification of the tight junctions theoretically offer the opportunity to regulate the diffusion barrier and then make it possible to investigate a permeation enhancer of low-bioavailability therapeutic agents. AT1002, a minimum biologically active fragment of zonula occludens toxin which reversibly opens intercellular tight junctions after binding to the Zonulin receptor, increased the transport of various molecular weight markers or low-bioavailability agents. The objective of this study was continuously to evaluate the permeation-enhancing ability of AT1002 in the presence of the bioadhesive agent, carrageenan after intranasal administration of the antiretroviral drug, ritonavir, and the permeation enhancement ratio compared with the previous results. The permeation-enhancing effect of AT1002 was significantly promoted by the bioadhesive agent, carrageenan. The administration of ritonavir with AT1002 and carrageenan resulted in a 2.55-fold increase in AUC(0-240min) and a 2.48-fold increase in C(max) compared with the control group. However, AT1002 in the absence of carrageenan did not produce a statistic enhancement in the absorption of ritonavir. Hence, AT1002 together with the addition of carrageenan may open a new approach of research in the tight junction modulated permeation enhancer, and allow the development of the mucosal drug delivery of therapeutic agents.

Recent progress in tight junction modulation for improving bioavailability

“…The significant intranasal absorption of high--molecularweight paracellular markers in combination with AT1002 suggests that AT1002 could be a valuable enhancer for therapeutic macromolecules or nasally administered vaccines [97]. Similar results have been found in studies with certain low--molecular-weight molecules (mannitol and ritonavir), where AT1002 enabled significant enhancement of nasal absorption [84,95]. 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].…”

“…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].…”

“…Cyclosporin A (+protease inhibitors) Rat Intraduodenal administration [69] Salmon calcitonin Rat Pulmonary (intratracheal instillation) [85] PEG4000 and inulin Rat Intranasal administration [97] Mannitol (+carrageenan, 5% dextrose) Rat Intranasal administration [84] Ritonavir (+carrageenan) Rat Intranasal administration [95] siRNA + Tat protein Mouse Dermal (tape-stripped back) [96] Inulin, calcitonin, saquinavir (+carrageenan or Na CMC)…”

The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease

“…38,39 AT1002 is currently being studied for applications to enhance oral drug absorption. 28,40,41 So far, gluten and bacteria (commensals and pathogenic) have been identified as triggers for small intestinal, luminal zonulin release from intact intestinal tissue and epithelial cell monolayers. 42,43 The effect of the bacterial strains on intestinal permeability correlated with luminal secretion of zonulin and could be blocked by AT1001 pretreatment.…”

Trends in drug delivery through tissue barriers containing tight junctions

“…In male Sprague-Dawley rats, intestinal uptake of cyclosporin A was increased by co-treatment with 10–40 mg/kg AT1002 (1.5 to 2.5-fold, 0–120 min after application) 88 . Nasal administration of the low bioavailability agent ritonavir (Abbott Laboratories), an antiretroviral drug to treat HIV infections, was increased 2.55-fold up to 240 min with AT1002 when co-administered with the bioadhesive polymer carrageenan 89 . One problem with the use of AT1002 is the instability of the peptide in neutral to basic pH conditions.…”