B. Mccormack et G. Gregoriadis, DRUGS-IN-CYCLODEXTRINS-IN-LIPOSOMES - A NOVEL CONCEPT IN DRUG-DELIVERY, International journal of pharmaceutics, 112(3), 1994, pp. 249-258
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.