Stability of a novel hexapeptide, (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt, with neurotensin activity, in aqueous solution and in the solid state.
The stability and some physicochemical properties of a novel hexapeptide, (Me)Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt (I), with neurotensin activity, were investigated. The degradation of I in aqueous solution was observed as a pseudo-first order reaction. By determining the degradation rate of I at various pH values, it was found that I was most stable at around pH 4. The activation energies of the degradation in aqueous solutions at pH 2.2, 6.1, 7.0 and 8.0 were 16.3, 22.2, 23.9 and 24.2 kcal/mol, respectively. The enzymatic hydrolysis of I was studied in vitro with a porcine liver esterase at 37 degrees C. The degradation of I in this system was observed as a pseudo-first order reaction. The degradation rate of I in the presence of the esterase was about 10000 times larger than the rate in a buffer solution. I in the solid state was stable under 65 degrees C and labilized by strong light and/or high humidity. The pKa1, pKa2 and pKa3 of I were 7.1, 10.0 and 11.3, respectively. The partition coefficients between n-octanol and the buffer solution at pH values ranging from 2 to 11 were measured. The partition coefficient increased with the increase of the pH value. But the value at pH 7.0 was 2.10 x 10(-2), which was very low. The solubility of I in aqueous solution was more than 10 mg/ml. From the results of the powder X-ray diffraction pattern, I in the solid state was found to be amorphous. The dissolution rates in the 1st and 2nd fluid of JPXI at 37 degrees C and 100 rpm were 19.4 and 9.0 mg/cm2.min, respectively.
Tokumura
T
T
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Tanaka
T
T
Sasaki
A
A
Tsuchiya
Y
Y
Abe
K
K
Machida
R
R
D000595:Amino Acid Sequence; D004355:Drug Stability; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000502:physiology*; D009842:Oligopeptides / Q000737:chemistry*; D011619:Psychotropic Drugs / Q000737:chemistry*; D012996:Solutions
D009842:Oligopeptides; D011619:Psychotropic Drugs; D012996:Solutions; C068195:methylarginyl-lysyl-prolyl-tryptophyl-tert-leucyl-leucyl-ethyl ester; D009496:Neurotensin