Effect of 2-hydroxypropyl-beta-cyclodextrin on the solubility, stability, and pharmacological activity of the chemical delivery system of TRH analogs
Wu, W.M.; Wu, J.; Bodor, N.
Die Pharmazie 57(2): 130-134
2002
ISSN/ISBN: 0031-7144 PMID: 11878189 Document Number: 550058
To improve the aqueous solubility and stability of the chemical delivery system (CDS) of the thyrotropin-releasing hormone (TRH) analogs, 2-hydroxypropyl-beta-cyclodextrin (HPBCD) has been attempted. TRH analogs were [Leu2]-TRH, [Nva2]-TRH and [Nva2, Pip3]-TRH. Excess amount of CDS was added in various HPBCD in water solutions (0%-50%, pH 6.5). The mixture was saturated by ultra-sonication for 1 h at 15 degrees C and filtered. The concentration of CDS in the filtrate (solubility) was determined with UV detector, and subsequently the stability was investigated. By HPBCD complexation, the aqueous solubility and stability (half-life) of CDS were significantly improved from undetectable levels to about 15 mg/ml and 30 h, respectively. In pH 6.5 and 7.4 HPBCD solution, the degradation of CDS was mainly via acid catalyzed water addition reaction, thus, e.g. [Leu2]-TRH-CDS was more stable in pH 7.4 than in pH 6.5 aqueous solutions. After lyophilizing the saturated CDSs in 50% HPBCD complex solutions, the amount of CDS in the complex was determined as 26.22, 26.79, and 30.34 mg/g for [Leu2]-TRH, [Nva2]-TRH and [Nva2, Pip3]-TRH, respectively. The half-life of [Leu2]-TRH-CDS/HPBCD solid complex at 25 degrees C, 4 degrees C and -15 degrees C was about 100 days, 440 days and no detectable change in three months, respectively. Argon protected condition did not improve the stability of lyophilized [Leu2]-TRH-CDS/HPBCD complex. Dimethyl sulfoxide although increased the solubility of [Leu2]-TRH-CDS in the 50% HPBCD solution by 1.3 times, significantly decreased its stability by 6.6 times. After intravenous administration of CDS (in 30% HPBCD) at a dose of 10 mumole/kg in mice, compared to the vehicle control or the same dose of [Leu2]-TRH (in 30% HPBCD), a significant increase in pharmacological effect (decrease in barbiturate-induced sleeping time) was observed. These results demonstrate the usefulness of cyclodextrin in the formulation of the CDSs of TRH analogs.