McCormack, Brenda; (2003) Cyclodextrin inclusion complexes in drug delivery: a role for liposomes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The lipophilicity of many therapeutic agents has compromised their use in parenteral delivery. Traditionally, hydrophobic compounds require formulating with organic co-solvents or non-ionic surfactants, which can cause local irritation or toxicity. Alternatively, drug solubility can be improved by forming cyclodextrin inclusion complexes, which, however, can be unstable in the biological milieu. This work has attempted to circumvent such problems by entrapping drug/cyclodextrin complexes into liposomes made by the DRV method. Lipophilic drugs such as dehydroepiandrosterone (DHEA), retinol (RET) and dexamethasone (DEX) were complexed with hydroxypropyl β-cyclodextrin (HPβ-CD), a water-soluble, non-toxic derivative of β-cyclodextrin, and complex formation verified by gel filtration chromatography (GFC), differential scanning calorimetry (DSC), and ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Optimum conditions for entrapment of complexes, in terms of phospholipid type, drug-to-lipid mass ratio and dilution factors during liposome formation, were determined. Comparative in vitro stability studies with buffer and blood plasma indicated that not only was lipid composition important for retention of entrapped complexes, as was the stability of the drug/HPβ-CD construct, but also that plasma factors were influential in liposome disruption and drug displacement. Blood clearance rates and biodistribution of free and entrapped complexes were monitored following intravenous injection into rats. Enhanced pharmacokinetics of entrapped complexed drugs was obtained compared to free drug complexes, as entrapped complexes assumed the fate of their liposomal carrier. Inclusion complexation followed by entrapment enabled greater amounts of lipophilic drugs to be delivered than when these drugs were incorporated as such into liposomal bilayers, thus improving drug bioavailability. Subcellular fractionation studies have indicated that drug/cyclodextrin complexes, delivered intracellularly via liposomes, may alter drug distribution due to sequestration of membrane substituents from internal organelles. These findings may have implications for drug delivery and targeting to specific intracellular locations.

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