A series of N-acetylated, non-alpha, aromatic amino acids was prepared and shown to promote the absorption of recombinant human growth hormone (rhGH) from the gastrointestinal tract. Seventy compounds in this family were tested in vivo in rats. Of the compounds tested, 4-[4-[(2-hydroxybenzoyl)amino]phenyl]butyric acid was identified as a preclinical candidate and was used to demonstrate the oral delivery of rhGH in primates. A significant positive correlation was found between the relative log k' of the delivery agents, as determined by HPLC on an immobilized artificial membrane (IAM) column, and serum rhGH concentrations following oral or colonic dosing in rats. Structure-activity relationships have also been developed on the basis of electronic effects and hydrogen-bonding characteristics of the aromatic amide substituents.

A family of novel compounds (delivery agents) that promote the gastrointestinal absorption of USP heparin in rats and primates has been discovered. The delivery agents in combination with heparin were administered either orally or intracolonically in an aqueous propylene glycol solution and caused dramatic increases in both plasma heparin concentrations (anti-Factor Xa) and clotting times (APTT). Using one of the most effective delivery agents in this series, an estimated relative bioavailability of 8% can be achieved following oral administration to cynomolgus monkeys. To establish a correlation between the in vivo data and an in vitro parameter, immobilized artificial membrane (IAM) chromatography was performed. Log relative k' values were correlated to the efficiency of oral heparin delivery.

No abstract

Heparin is the anticoagulant of choice for hospitalized patients, but it is dosed only by injection because it is not absorbed following oral administration. We have discovered and prepared compounds (delivery agents) that facilitate the gastrointestinal absorption of heparin in rats, monkeys, and humans when given orally. We are currently developing a parallel synthesis approach to increase our delivery agent screening throughput in vivo. This approach has been used to produce micromolar quantities of compounds for testing in rats in a 5 x 5 parallel synthesis array. Using an amine benzoylation reaction sequence, 10 mixtures were prepared. These mixtures contained equal weight quantities of five N-substituted, non-alpha, amino acid delivery agents. Each of these mixtures was orally administered to rats in combination with heparin, and plasma clotting times (APTT) were measured to determine activity. Deconvolution of the data accurately identified the most active individual components. Independent synthesis of these compounds verified their activity. This parallel synthesis approach is an effective tool for the screening of oral heparin delivery agents and has increased screening throughput significantly.

SI of any solution, including normal saline, seems to have a minor but detectable effect on the normal physiology of the lung. SI of positive control solutions resulted in most markers of immunity and lung injury being significantly elevated, notably enzyme activity and white cell infiltrate. In contrast, SI of INS produced a response similar to that of SAL. SI of INMA resulted in a small transient response characterized by a slight increase in the proportion of neutrophils at 24 h, which decreased with time and was comparable to that of SAL at 72