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.

The Wigner regime of a system of electrons in an external field is characterized by a low electron density and a high electron-interaction energy relative to the kinetic energy. The low correlation regime is in turn described by a high electron density and an electron-interaction energy smaller than the kinetic energy. The Wigner regime of a nonuniform electron density system is investigated via quantal density functional theory (QDFT). Within QDFT, the contributions of electron correlations due to the Pauli exclusion principle, Coulomb repulsion, and correlation-kinetic effects are separately delineated and explicitly defined. The nonuniform electron density system studied is that of Hooke’s atom in the Wigner regime for which the exact wave function is derived. As such the results of the QDFT analysis are exact. It is observed that in comparison to the low correlation case, not only is the electron-interaction energy greater than the kinetic energy as a fraction of the total energy, but so are its individual Hartree, Pauli, and Coulomb components. The ionization potential as a fraction of the total energy too is greater. But most significantly, in the Wigner regime, the correlation-kinetic energy as a fraction of both the electron-interaction and total energy is substantially greater than in the low correlation case. Hence, we propose that the Wigner regime now also be characterized by a high correlation-kinetic energy. The kinetic energy as a fraction of the total energy, however, is less than in the low correlation case. This fact and the high correlation-kinetic energy value in the Wigner regime is explained by the new concept of ‘quantal compression’ of the kinetic energy density derived from QDFT. The corresponding results for the low correlation case are in turn a consequence of a ‘quantal decompression’ of the kinetic energy density. From the QDFT analysis, the exact values for the Kohn-Sham theory ‘exchange-correlation’ and ‘correlation’ energy functionals of the density, and their respective functional derivatives are also obtained. These results ought to be of value in the construction and testing of new approximate energy functionals valid for the Wigner regime.

A series of benzoylated and phenylsulfonylated amino acids are novel, low molecular weight, self-assembling molecules. At low pH, these compounds form microspheres that dissolve readily under neutral conditions. In a given synthetic series, those molecules with low aqueous solubility formed microspheres more readily than did the molecules possessing high water solubility, suggesting that the hydrophobicity of these compounds contributes to the ability to form microspheres. In addition, molecular modeling studies on selected compounds have shown that microsphere formation may depend also on various aromatic ring and dipole-dipole interactions, which could effect the extent and types of favorable stacking conformations between molecules. The microspheres prepared from these compounds have been used to effect the oral delivery of salmon calcitonin, a model protein drug, in both rodents and primates.

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