title: Effect of 2-hydroxypropyl-beta-cyclodextrin on the solubility, stability, and pharmacological activity of the chemical delivery system of TRH analogs.
abstract: 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.
authors.affiliation: Center for Drug Discovery, University of Florida, Gainesville, FL, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D003505:Cyclodextrins; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D016503:Drug Delivery Systems; D004355:Drug Stability; D005079:Excipients; D005612:Freeze Drying; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D051379:Mice; D012890:Sleep / Q000187:drug effects; D012995:Solubility; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins
chemical_list: D001463:Barbiturates; D003505:Cyclodextrins; D005079:Excipients; D012996:Solutions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D013973:Thyrotropin-Releasing Hormone; D004121:Dimethyl Sulfoxide