Pharmaceutical Manufacturing Handbook: Production and

454 LIPOSOMES AND DRUG DELIVERY
a similar manner, higher amounts of calcitonin were encapsulated in positively
charged compared to neutral liposomes [104] while the highest loading of indomethacin
in liposomes was obtained in the following order: positively charged >
negatively charged > neutral liposomes [105] .
Cholesterol and α - tocopherol are used quite often to increase the rigidity and
stability of liposomal membranes [88, 106 – 108] . In most cases cholesterol appears
to improve the encapsulation of both hydrophilic and hydrophobic compounds.
However, if the drug is lipophilic and partitions in the liposome membrane, there
is a good chance that it might be displaced by adding increasing amounts of cholesterol
in the bilayer (as observed in the case of dexamethasone encapsulating liposomes
in our laboratory).
A novel system for enhancing the drug loading of lipophilic drugs combining
liposomes and cyclodextrin – drug complexes by forming drug - in - cyclodextrins -
in - liposome preparations has been proposed [109 – 111] . Cyclodextrins (CDs) are
hydrophobic, cavity - forming, water - soluble oligosaccharides that can accommodate
water - insoluble drugs in their cavities, increasing their water solubility. The basic
intention is to encapsulate a stable water - soluble drug – cyclodextrin complex in the
aqueous compartments of liposomes (Figure 6 ). As will be discussed below, this
system can also serve as a method to increase the retention of lipophilic drugs in
diluted liposome dispersions.
Finally, remote loading and active loading [11] are other methods used to achieve
high trapping effi ciency in liposome formulations, but unfortunately they can only
be applied to a small number of drugs with specifi c physicochemical properties. This
technique will be discussed below in Section 5.3.2.3 .
Lipid bilayer
Aqueous interior
Drug–CD
complex
(High aqueous solubility)
= CD = Drug
(Low aqueous solubility)
FIGURE 6 Representation of drug in – cyclodextrin in liposome technique for encapsulation
of lipophilic drugs in aqueous interior of vesicles. Drug molecules have low aqueous
solubility and thus cannot be encapsulated in the aqueous compartment of the vesicle.
However, the drug – cyclodextrin complex has high aqueous solubility and can thus be encapsulated
in high concentrations in the vesicles.