Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Abstract

Although protein drugs are powerful biologic therapeutics, they cannot be delivered orally because their large size and hydrophilicity limit their absorption across the intestinal epithelium. One potential solution is the incorporation of permeation enhancers into oral protein formulations; however, few have advanced clinically due to toxicity concerns surrounding chronic use. To better understand these concerns, we conducted a 30‐day longitudinal study of daily oral permeation enhancer use in mice and resultant effects on intestinal health. Specifically, we investigated three permeation enhancers: sodium caprate (C 10 ), an industry standard, as well as 1‐phenylpiperazine (PPZ) and sodium deoxycholate (SDC). Over 30 days of treatment, all mice gained weight, and none required removal from the study due to poor health. Furthermore, intestinal permeability did not increase following chronic use. We also quantified the gene expression of four tight junction proteins (claudin 2, claudin 3, ZO‐1, and JAM‐A). Significant differences in gene expression between untreated and permeation enhancer‐treated mice were found, but these varied between treatment groups, with most differences resolving after a 1‐week washout period. Immunofluorescence microscopy revealed no observable differences in protein localization or villus architecture between treated and untreated mice. Overall, PPZ and SDC performed comparably to C 10 , one of the most clinically advanced enhancers, and results suggest that the chronic use of some permeation enhancers may be therapeutically viable from a safety standpoint.

Recent Advances in Oral and Transdermal Protein Delivery Systems

“…To date, numerous permeation enhancers, including ionic liquids, [16, 37] cell‐penetrating peptides (CPPs), [38] fatty acids, [39] ethylenediaminetetraacetic acid (EDTA), [40] and bile salts, [41] are reported to improve the oral absorption of proteins in preclinical studies. The majority of oral protein delivery platforms currently in clinical trials are based on permeation enhancers that are generally recognized as safe (GRAS) without toxicity concerns [36a, 42] . In 2019, the FDA approved oral semaglutide based on the absorption enhancer of sodium N ‐[8‐(2‐hydroxybenzoyl) aminocaprylate] (SNAC) platform for type 2 diabetes.…”

Oral delivery of nanomedicine for genetic kidney disease

“…Although kidney-targeting peptide amphiphile micelles (KMs) homed to the kidneys in vivo upon intravenous (IV) injection, IV administration is not practical for chronic diseases such as ADPKD that progress over a lifetime ( 34 , 35 ). To meet the unmet challenges required for inherited and lifelong diseases and improve the bioavailability of drugs for chronic kidney diseases such as ADPKD, herein, we developed a biomaterials-based strategy for oral administration of kidney-targeting nanoparticles and hypothesized that encapsulating KMs loaded with metformin (KM -met ) into chitosan particles (CP) would enable enhanced nanoparticle bioavailability and drug delivery to the kidneys (Scheme 1 ) ( 36 , 37 ). We chose chitosan for developing our oral delivery strategy as chitosan is a biocompatible biomaterial that is naturally derived from crustacean shells and has been reported to improve the drug bioavailability upon oral administration due to its high stability in acidic conditions, like that of the stomach, and its mucoadhesive properties that enable high absorption in the intestines ( 38–40 ).…”