Lipophilic molecules, delivery

In general, the blood-brain barrier (BBB) is only permeable to lipophilic molecules of molecular weight <600 Da, while even small water-soluble molecules generally cannot be transported [21]. This would preclude the direct delivery of ASO to the brain from the systemic circulation without the assistance of specialized drug delivery systems. 

Liposomes are phospholipid vesicles composed of lipid bilayers enclosing an aqueous compartment. Hydrophilic molecules can be encapsulated in the aqueous spaces, and lipophilic molecules can be incorporated into the lipid bilayers. Liposomes, in addition to their use as artificial membrane systems, are used for the selective delivery of antioxidants and other therapeutic dmgs to different tissues in sufficient concentrations to be effective in ameliorating tissue injuries (Stone et al., 2002). Antioxidant liposomes containing combinations of water- and lipid-soluble antioxidants may provide a unique therapeutic strategy for mustard gas exposure because (1) the antioxidants are nontoxic and could, therefore, be used at the earliest stages of exposure (2) the liposomes themselves are composed of nontoxic, biodegradable, and reusable phospholipids ... 

Dentinger PM, Simmons BA, Cruz E, Sprague M (2006) DNA-mediated delivery of lipophilic molecules via hybridization to DNA-based vesicular aggregates. Langmuir 22 2935-2937... 

Such a parabolic relation has the following incidence on drug delivery a molecule with a low partition coefficient will partition slowly from water into a lipid membrane. If the receptor is within or beyond that membrane, such a molecule will have a low probability of reaching it in the time interval under study. Conversely, molecules which are highly lipophilic will readily partition into the first of a series of lipid membranes, but will be held there and thus slowed down in their random walk to their site of action. Hence, optimal transport conditions are clearly achieved by drugs of intermediate partition coefficient, with no transfer step being too low. 

Transdermal delivery is suitable for small, generally lipophilic, potent molecules that require low input rates to achieve effective plasma concentrations. There may be a slow rate of increase of concentration if the drug forms a depot in the skin. Depot formation will also result in a slow decrease in concentration when the system is removed from the skin. These disadvantages can be overcome by the use of iontophoresis, by which the molecules are actively carried across the skin by a small electrical current. This provides a faster and more controllable transfer of drug. Intramuscular/Subcutaneous... 

The ultimate test of a QSAR is of course to make predictions and verify them experimentally. More compounds will thereby be prepared, the data set will be expanded, the QSAR will be refined and its limitations found. No QSAR goes on forever , e.g. a linear relationship between receptor binding and lipophilicity (as log P) will break down when the molecule either becomes too big to fit within the receptor site, or too insoluble for delivery. 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

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