The effects of cyclodextrins on drug release from fatty suppository bases: III. Application of cyclodextrin derivatives

The complexation of both n-butyl-4-aminobenzoate and diazepam with dimethyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin, respectively, was studied. Solid complexes were prepared by freeze-drying. The complexes were incorporated in fatty suppositories and drug release was studied, both in vitro and in vivo. The dm-beta-cyclodextrin was found to be unsuitable for use in fatty suppositories because of dissolution of the complex in the fatty suppository base. This in contrast to the non-lipid-soluble hp-beta-cyclodextrin complexes, which improved drug release from the suppositories by the same release mechanism as native cyclodextrins. Sedimentation of the solid complex particles from the molten lipid layer is followed by fast dissolution in the aqueous layer. In addition, back diffusion of the drug in the suppository base is suppressed by high stability constants of the complex. The in vivo situation was studied by the administration of suppositories containing diazepam only, the diazepam-gamma-cyclodextrin complex and the diazepam-hp-beta-cyclodextrin complex, respectively, to human volunteers. Diazepam absorption was found to be highest for the suppository containing diazepam-hp-beta-cyclodextrin complex. The improvement in drug release from the suppository was mainly caused by the increased dissolution rate of the complex, The higher complex stability constant was of little influence in vivo. The overall improvement in bioavailability was consequently smaller than expected from the in vitro studies.