Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.