N-Acylated .alpha.-Amino Acids as Novel Oral Delivery Agents for Proteins

Abstract

A series of N-acylated alpha-amino acids were synthesized and shown to improve the oral delivery of two protein drugs, salmon calcitonin (sCT) and interferon-alpha. Forty-five compounds in this series were tested in vivo in rats and primates. A significant positive correlation was found between the log P of the acylated amino acids and the decrease in serum calcium following oral dosage of sCT in rats. Such a correlation was not found for interferon-alpha. These derivatized amino acids only weakly inhibited the activity of trypsin or leucine aminopeptidase. Histological examinations of rat intestinal tissue after oral dosing of acylated amino acid/protein combinations revealed no detectable pathology.

4-[4-[(2-Hydroxybenzoyl)amino]phenyl]butyric Acid as a Novel Oral Delivery Agent for Recombinant Human Growth Hormone

“…These compounds were designed as part of an effort to expand upon our earlier leads, which were N-acylated, R-amino acids. 16 Of the current compounds, 2 has been identified as a preclinical candidate (Table 1).…”

Intestinal permeation enhancers for oral peptide delivery

“…SAR testing indicated that lipophilicity [354] and hydrogen bonding [355] may play a role in intestinal permeation enhancement induced by Eligen®, although a consistent effect was not observed. A preliminary screen of 11 carriers showed that an optimal bell-shaped window of lipophilicity was required to improve oral heparin absorption [356].…”

Nanopreparations for Oral Administration

“…3 Generally, penetration enhancers work by physiological alteration of the epithelium to exploit transport mechanisms. 66 Exploited transport mechanisms can be sub-grouped into methods that disrupt the structural integrity of the epithelial layer, decrease the mucous viscosity, open tight junctions or increase membrane fluidity. 3 Penetration enhancement principles assume a sufficient quantity of therapeutic agent and penetration enhancers at the site of absorption.…”