Thermo-reversible flurbiprofen liquid suppository with HP-beta-CD as a solubility enhancer: improvement of rectal bioavailability

Abstract

The purpose of this work was to develop a thermo-reversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen. Cyclodextrin derivatives such as alpha-, beta-, gamma-cyclodextrin and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used to enhance the aqueous solubility of flurbiprofen. The effects of HP-beta-CD and flurbiprofen on the physicochemical properties of liquid suppository were then investigated. Pharmacokinetic studies were performed after rectal administration of flurbiprofen liquid suppositories with and without HP-beta-CD or after intravenous administration of commercial Lipfen(A (R)) (flurbiprofen axetil-loaded emulsion) to rats, and their pharmcokinetic parameters were compared. HP-beta-CD decreased the gelation temperature and reinforced the gel strength and bioadhesive force of liquid suppository, while flurbiprofen was opposed to HP-beta-CD. Thermo-reversible flurbiprofen liquid suppository showed the physicochemical properties suitable for rectal administration. The flurbiprofen liquid suppository with HP-beta-CD showed significantly higher plasma levels, AUC and C-max of flurbiprofen than those of the liquid suppository without HP-beta-CD, indicating that flurbiprofen could be well absorbed due to the enhanced solubility by formation of inclusion complex. Moreover, the flurbiprofen liquid suppository with HP-beta-CD showed an excellent bioavailability in that the AUC of flurbiprofen after its rectal administration was not significantly different from that after intravenous administration of commercial Lipfen(A (R)). It is concluded that HP-beta-CD could be a preferable solubility enhancer for the development of liquid suppository containing poorly water-soluble drugs.