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

TOKUMURA T., TANAKA Tomohide, SASAKI Atsushi, TSUCHIYA Yutaka, ABE Kouichi, MACHIDA Ryoichi

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 24.2kcal/mol, respectively.The enzymatic hydrolysis of I was studied in vitro with a porcine liver esterase at 37℃. 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℃ and labilized by strong light and/or high humidity. The pK_<a1>, pL_<a2> and pK_<a3> 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 2.10×10^<-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 differaction pattern, I in the solid state was found to be amorphous.The dissolution rates in the 1st and 2nd fluid of JPXI at 37℃ and 100 rpm were 19.4 and 9.0 mg/cm^2・min, respectively.

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

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