DRUGS-IN-CYCLODEXTRINS-IN-LIPOSOMES - A NOVEL CONCEPT IN DRUG-DELIVERY

Inclusion complexes of tritiated dehydroepiandrosterone (DHEA), retino l (R) and retinoic acid (RA) were formed with C-14-labelled 2-hydroxyp ropyl-beta-cyclodextrin (HP beta CD) or unlabelled beta-cyclodextrin ( beta CD) polymers 2009 and 2010 (Mol. Wt 4000-4500 and 8700, respectiv ely) at various molar ratios. Formation of inclusion complexes was con firmed by the complete or partial solubilization of the drugs used and by the simultaneous elution of drug and HP beta CD radioactivities fo llowing molecular sieve chromatography of the complex solutions. Inclu sion complex solutions (also containing 'void' cyclodextrins) were sub sequently entrapped into dehydration-rehydration vesicles (DRV liposom es). Ratios of entrapment values (% of amounts used) for drugs and cyc lodextrin (HP beta CD) approximating unity were taken to denote entrap ment that did not discriminate between complexes and void cyclodextrin . Near unity ratios and highest entrapment values (e.g., up to 32.3 +/ - 11.9% (DHEA) and 31.9 +/- 11.8% (HP beta CD) of the materials used; distearoyl phosphatidylcholine (DSPC) DRV) were achieved with liposome s made of phospholipids with a high gel liquid crystalline transition temperature (T-c) or, when equimolar (to the phospholipid) cholesterol was also present, with all phospholipids, regardless of their T-c. Wh en DSPC liposomes (without or with equimolar cholesterol) containing d rug (DHEA, R or RA) complex solutions with cyclodextrins were exposed to rat blood plasma at 37 degrees C for up to 60 min, cyclodextrin (HP beta CD) retention was nearly complete (0.7-11.9% released at 60 min) . However, release of drugs was considerable with values being signifi cantly greater for DHEA (60.2-62.0%) than for R or RA (26.6 and 26.8%, respectively). Experiments with DRV containing both carboxyfluorescei n (CF) (as a marker of vesicle stability) and inclusion complex soluti ons revealed that entrapped cyclodextrins do not destabilize liposomes . Instead, data suggest that during or after the entrapment of complex solution into liposomes, some of the included drug is displaced from the cyclodextrin cavity by phospholipid and/or cholesterol (to a degre e probably dependent on the stability constant of the complex) to end up in the lipid bilayer in a state which, on incubation, ensures rapid release into the media. Results suggest that entrapment of water-inso luble (or certain soluble drugs) in the form of cyclodextrin-inclusion complexes into the aqueous phase of liposomes may circumvent some of the problems associated with their entrapment as such.